PT1353919E - Novel quinuclidine derivatives and medicinal compositions containing the same - Google Patents

Description

The present invention relates to novel quinuclidine derivatives and medicinal compositions comprising the same " novel pharmaceutical derivatives to some of the pharmaceutical

This invention relates to quinuclidine therapeutically useful, for the preparation thereof and compositions containing.

The novel structures according to the invention are antimuscarinic agents with a potent and long lasting effect. In particular, these compounds show a high affinity for muscarinic M3 receptors. This muscarinic receptor subtype is present in glands and smooth muscle and mediates the excitatory effects of the parasympathetic system on glandular excretion and contraction of visceral smooth muscle (Chapter 6, Cholinergic Transmission, in HP Range et al., Pharmacology, Churchill Livingstone, New York, 1995).

M3 antagonists are therefore known to be useful in treating diseases characterized by an increase in parasympathetic tonus, by excessive glandular excretion or by contraction of smooth muscle (RM Eglen and SS Hegde (1997), Drug News Perspec., 10 (8): 462-469). 2 ΡΕ1353919

Examples of such diseases are respiratory diseases such as chronic obstructive pulmonary disease (COPD), bronchitis, bronchial hyperreactivity, asthma, cough and rhinitis; urological diseases, such as urinary incontinence, polaciria, neurogenic or unstable bladder, cytospasm and chronic cystitis; gastrointestinal diseases, such as irritable bowel syndrome, spasmodic colitis, diverticulitis, and peptic ulceration; and cardiovascular diseases, such as vaginally induced sinusoidal bradycardia (Chapter 7, Muscarinic Receptor Agonists and Antagonists, in Goodman and Gilman's Pharmacological Basis of Therapeutics, 10th edition, McGraw Hill, New York, 2001).

The compounds of the invention may be used alone or in combination with other drugs usually considered to be effective in treating such diseases. For example, these may be administered in combination with the β2 agonists, steroids, antiallergic drugs, phosphodiesterase IV inhibitors and / or leuko-triene D4 (LTD4) antagonists, for simultaneous, separate or sequential use in the treatment of a disease respiratory. The claimed compounds are useful for the treatment of respiratory diseases detailed above in association with β2-agonists, steroids, antiallergic drugs or phosphodiesterase IV inhibitors.

Compounds with related structures were disclosed as anti-cholleric and / or anti-spasmodic agents in various patents.

For example, FR 2012964 discloses quinuclidinol derivatives of formula

wherein R 1 is H, OH or an alkyl group having 1 to 4 carbon atoms; R1 is a phenyl or thienyl group and R2 is a cyclohexyl, cyclopentyl or thienyl group, or, when R is H, R1 and R2 together with the carbon atom to which they are attached form a tricyclic group of formula

wherein X is -O-, -S- or -CH2-, or an acid or quaternary ammonium addition salt thereof.

In U.S. Patent 4,465,834 a class of anticholinergic drugs having the formula ΡΕ1353919 4 C00R3 R2 as described, wherein R1 is a branched carbocyclic or aliphatic group of 3 to 8 carbon atoms (such as phenyl, cyclohexyl , cyclopentyl, cycloheptyl and isopropyl), R 2 is a branched or straight-chain group containing from 3 to 10 carbon atoms with 1 or 2 olefinic or acetylene linkages, or is a phenylethynyl, styryl or ethynyl group, and R 3 is an alkyl or cyclic group of 4 to 12 carbon atoms, containing a tertiary amino nitrogen. The compounds of the invention are also claimed either as the free base or as acid addition and quaternary ammonium addition salts thereof.

In U.S. Patent 4,843,074 there are disclosed products of formula

piperidinyl, where X = H, halogen, hydroxyl alkyl and R = morpholinyl, thiomorpholinyl, 5α, 13β, 13-dioxa-8-azaspiro [4,5] decanyl, 4- (2,6-dimethylmorphol- milo), 4-cetopiperidinyl, 4-hydroxypiperidinyl, 4-substituted piperazinyl. Quaternary lower alkyl halide salts and pharmaceutically acceptable acid addition salts are included in the invention. U.S. Patent 4,644,003 discloses 3-quiniclidinol esters of alpha-disubstituted glycolic acids

R 1 is and pharmaceutically acceptable salts thereof, wherein R 2 is phenyl, unsubstituted or substituted with up to three substituents including alkoxy, halogen, nitro, amino, alkylamino, dialkylamino, acylamino, and trifluoromethyl; wherein R1 is hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, alkyloxyalkyl, cycloalkyloxyalkyl, haloalkyl or haloalkenyl.

WO 92/04346 discloses compounds

PH D -He *

And pharmaceutically acceptable salts thereof, wherein X is a (optionally substituted) phenyl or thienyl group and " Het " is either (a) a five-membered nitrogen-containing heterocyclic group, (b) an oxadiazolyl or thiadiazolyl group, or (c) a six-membered nitrogen-containing heterocyclic group in is 1 or 2. (For a more detailed description see the abovementioned publication).

Azonibicyclic compounds of general structure related to the compounds of the invention are described in WO 01/04118. The present invention provides novel quinuclidine ester derivatives with potent antagonist activity at M3 muscarinic receptors having the chemical structure described in formula (I):

m

wherein B is a phenyl ring, a 5- to 10-membered heteroaromatic group containing one or more heteroatoms selected from N, O, O, or a naphthalenyl, 5,6,7,8-tetrahydronaphthalenyl, benzo [1 , 3] dioxolyl, or a biphenyl group; 7 ΡΕ1353919

R 1, R 2 and R 3, each independently represents a hydrogen or halogen atom, or a phenyl group, a -OR 7, -SR 7, -NR 7 R 8, -NHCOR 7, -CONR 7 R 8, -CN, -NO 2, - COOR 7, or CF3, or a linear or branched C1 to C6 alkyl group which is substituted or unsubstituted with one or more halogen atoms, hydroxyl groups or C1 to C6 alkoxy groups, wherein R7 and R8 each independently represent a hydrogen atom a straight chain or branched C1 to C8 alkyl group, or together form a C1 to C8 alicyclic ring; or R1 and R2 together form a C5 to C14 or C3 to C8 alicyclic aromatic ring or a 5- to 10-membered heterocyclic group containing one or more heteroatoms selected from N, S and O; n is an integer from 0 to 4; A represents a group selected from -CH2-, -CH = CHR9-, -CR9 = CH-, -CR9R10-, -CO-, -O-, -S-, -S (O) -, -S (O) 2 and NR9, wherein R9 and R10, each independently, represent a hydrogen atom, a linear or branched C1 to C6 alkyl group, or together form a C3 to C8 alicyclic ring; m is an integer from 0 to 8, provided that when m = 0, A is not -CH 2 -; p is an integer of 1 to 2 and the substitution in the bicyclic azonia ring may be in the 2, 3 or 4 position ΡΕ1353919 including all possible configurations of the asymmetric carbons; R 4 represents a group of structure:

wherein R11 represents a hydrogen or halogen atom, a hydroxide group, a C1 -C6 alkoxy group, a nitro group, a cyano group, -CO2 R12 or -NR12 R13 where R12 and R13 are identical or different and are selected from hydrogen and straight or branched chain C1 to C6 alkyl groups or a linear or branched C1 to C6 alkyl group which is unsubstituted or substituted with one or more halogen atoms, hydroxyl groups or C1 to C6 alkoxy groups represents a alkyl group of 1 to 7 carbon atoms, an alkenyl group containing 2 to 7 carbon atoms, an alkynyl group containing 2 to 7 carbon atoms, a cycloalkyl group of 3 to 7 carbon atoms, or a group of formula

R 1 where q = 1 or 2 and R 11 is as defined 9 ΡΕ 13551919 above; R 6 represents a hydrogen atom, a hydroxide group, a methyl group or a -CH 2 OH group. The asymmetric carbon atom at the alpha position to the ester group which is substituted with R4, R5 and R6 may have R or S configuration. X represents a pharmaceutically acceptable anion of a mono or polyvalent acid.

In the quaternary ammonium compounds of the present invention represented by formula (I), one equivalent of an anion (X ") is associated with the positive charge of the N atom. X 'may be an anion of various mineral acids, such as, for example , chloride, bromide, iodide, sulfate, nitrate, phosphate, or an anion of an organic acid, such as, for example, acetate, maleate, fumarate, citrate, oxalate, succinate, tartrate, malate, mandelate, trifluoroacetate, methanesulfonate and p -toluenesulfate. X "is preferably an anion selected from chloride, bromide, iodide, sulfate, nitrate, acetate, maleate, oxalate, succinate or trifluoroacetate. More preferably, X1 is chloride, bromide, trifluoroacetate or methanesulfonate.

Compounds of the present invention represented by formula (I) described above, which may have one or more asymmetric carbons, include all possible stereoisomers. The single isomers and mixtures of the isomers are 10 ΡΕ1353919 within the domain of the present invention.

As used herein, an alkyl group is typically a lower alkyl group. A lower alkyl group preferably contains 1 to 8, preferably 1 to 6 and more preferably 1 to 4 carbon atoms. In particular it is preferred that such an alkyl group be represented by a methyl, ethyl, propyl, including i-propyl, or butyl group including n-butyl, sec-butyl and tert-butyl. An alkyl group containing 1 to 7 carbon atoms as mentioned herein such as those represented by R 5 may be a C 1-4 alkyl group as mentioned above or a linear or branched pentyl, hexyl or heptyl group.

Optionally, the substituted lower alkyl groups mentioned herein include straight or branched chain alkyl groups containing from 1 to 6, preferably from 1 to 4 carbon atoms, as mentioned above, which may be unsubstituted or substituted at any position with one or more substituents; for example, with 1, 2 or 3 substituents. Where two or more substituents are present, each substituent may be the same or different. The substituent (s) are typically halogen atoms or hydroxide or alkoxy groups, preferably hydroxide or alkoxy groups.

Alkenyl groups having 2 to 7 carbon atoms mentioned herein, such as those represented by the R 5 group, are straight or branched groups, such as ethenyl, or propenyl, butenyl, pentenyl, hexenyl or heptenyl groups. The double bond may be at any position on the alkenyl group, such as on a terminal bond.

Alkynyl groups having 2 to 7 carbon atoms mentioned herein, such as those represented by the group R 5 are linear or branched groups, such as the ethynyl, propenyl, butynyl, pentynyl, hexynyl or heptynyl groups. The triple bond may be in any position on the alkenyl group, such as on a terminal bond.

The alkoxy groups mentioned herein, such as those which may be present in group B, are typically lower alkoxy groups, i.e., groups containing from 1 to 6 carbon atoms, preferably from 1 to 4 carbon atoms, the straight or branched chain hydrocarbon chain. Preferred alkoxy groups include methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, sec-butoxy and t-butoxy.

The cycloalkyl groups and alicyclic groups mentioned herein, unless otherwise specified, typically contain from 3 to 8 carbon atoms, preferably from 3 to 6 carbon atoms. Cycloalkyl groups and alicyclic rings of 3 to 6 carbon atoms include cyclopropy, cyclobutyl, cyclopentyl and cyclohexyl. Cycloalkyl groups containing from 3 to 7 carbon atoms include cycloalkyl groups of 3 to 6 carbon atoms and cyclohexyl cyclohexyl. The aromatic ring mentioned with respect to R1 and R2 contains 5 to 14, preferably 5 to 10 carbon atoms. Examples of aromatic groups include cyclopentadienyl, phenyl and naphthalenyl.

A heterocyclic or heteroaromatic group mentioned herein is typically a 5- to 10-membered group such as a 5-, 6- or 7- membered group containing one or more heteroatoms selected from N, O and O. Typically, 1,2 , 3 or 4 heteroatoms, preferably 1 or 2 heteroatoms. A heterocyclic or heteroaromatic group may be a single ring or two or more fused rings, wherein at least one ring contains a heteroatom. Examples of heterocyclic groups include piperidyl, pyrrolidyl, piperazinyl, morpholinyl, thiomorpholinyl, pyrrolyl, imidazolyl, imidazolidinyl, pyrazinyl, indolinyl, isoindolinyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolizinyl, isoindolyl, indolyl, indazolyl, purinyl , quinolizinyl, isoquinolino, quinolinyl, phthalazinyl, naphthyridinyl, quinoxalinyl, quinazolinyl, cinilinyl, pteridinyl, quiniclidinyl, triazolyl, pyrazylyl, tetrazolyl, and thienyl. Examples of heteroaromatic groups include pyridyl, thienyl, furyl, pyrrolyl, imidazolyl , benzothiazolyl, pyridinyl, pyrazolyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolyl, indazolyl, purinyl, quinolinyl, isoquinolyl, phthalazinyl, naphthyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, triazolyl and pyrazolyl.

As used herein, a halogen atom includes a fluorine, chlorine, bromine or iodine atom, typically a fluorine, chlorine or bromine atom.

Preferred compounds of formula (I) are those in which B represents a phenyl, pyrrolyl, thienyl, furyl, biphenyl, naphthalenyl, 5,6,7,8-tetrahydronaphthalenyl, benzo [1,3] dioxolyl, imidazolyl or benzothiazolyl, in particular a phenyl, pyrrolyl, thienyl, furyl, biphenyl, naphthalenyl, 5,6,7,8-tetrahydronaphthalenyl or benzo [1,3] dioxolyl group, such as a phenyl, thienyl or pyrrolyl group. B may be unsubstituted or substituted with one, two or three groups (R1 to R3) which may be in any position on the ring. Typically is unsubstituted or substituted with one group, for example, when B is a phenyl group this may be substituted at the 2, 3 or 4 position. Typically R1, R2 and R3, each independently, represent a hydrogen or halogen atom or a hydroxide, methyl, tert-butyl, -CH 2 OH, 3-hydroxypropyl, -OMe, -NMe 2, -NHCOMe, -CONH 2, -CN, -NO 2, -COOMe or CF 3 group, in particular a hydrogen, fluorine or chlorine, or a hydroxide, methyl, -CH 2 OH, -OMe, -NMe 2, -NHCOMe, -CONH 2, -CN, -NO 2, -COOMe or CF 3 group. The most preferred R1, R2 and R3 groups are hydrogen, fluorine, chlorine or hydroxide. 14 ΡΕ1353919

Examples of substituted phenyl groups which may represent B are tolyl including o-, m- and p-tolyl, 3-cyanophenyl, 2-, 3- and 4-hydroxyphenyl and 2-, 3- and 4-fluorophenyl.

Preferred compounds of formula (I) are those wherein n = 0 or 1; m is an integer from 1 to 6, particularly 1, 2 or 3 and A is -CH 2 -, -CH = CH-, -CO-, -NMe-, -O- or -S-, in particular a -CH 2 -, -CH = CH-, -o- or -S- group, for example a -CH 2 -, -CH = CH-, or -O- group.

The most preferred salts of formula (I) are those in which the azoniabicyclo group is substituted on the nitrogen atom with a 3-phenoxypropyl, 2-phenoxyethyl, 3-phenylallyl, phenethyl, 4-phenylbutyl, 3-phenylpropyl, 3- 2-benzyloxyethyl, 3-pyrrol-1-ylpropyl, 2-thien-2-ylethyl, 3-thien-2-ylpropyl, 3-phenylaminopropyl, 3- - (methylphenylamino) propyl, 3-phenylsulfanylpropyl, 3-o-tolyloxypropyl, 3- (2,4,6-trimethylphenoxy) propyl, 3- (2- tert -butyl-6-methylphenydoxy) propyl, 3- (naphthalen-1-yloxy) propyl, 3- (5,6,7,8-tetrahydronaphthalen-2-yloxy) propyl, 3- (naphthalen-2-yloxy) propyl, 3- (naphthalen-1-yloxy) propyl, 3- (2-chlorophenoxy) propyl, 3- (2,4-difluorophenoxy) propyl, 3- (3-trifluoromethylphenoxy) propyl, 3- (3-cyanophenoxy) propyl, 3- (4-cyanophenoxy) propyl, 3- (3-methoxyphenoxy) propyl, 3- (4-methoxyphenoxy) propyl, 3- (benzo [1,3] dioxol-5-yloxy) propyl, 3- (2-carbamoylphenenoxy) propyl, 3- (3- dimethylaminophenoxy) propyl, 3- (4-nitrophen-15β, 13β, 19-ethoxy) propyl, 3- (4-acetylaminophenoxy) propyl, 3- (4-methoxycarbonylphenoxy) propyl, 3- [4- (3-hydroxypropyl) phenoxy] propyl, 3- (2-hydroxymethylphenoxy) propyl, 3- (3-hydroxymethylphenoxy) propyl, 3- (4-hydroxymethyl-phenoxy) propyl, 3- (2-hydroxyphenoxy) propyl, 3- (4-hydroxyphenoxy) propyl, 3- (3-hydroxyphenoxy) propyl , 4-oxo-4-thien-2-ylbutyl, 3- (1-methyl- [1H] -imidazol-2-ylsulfanyl) propyl, 3- (benzothiazol-2-yloxy) propyl, 3-benzyloxypropyl, 6- 4- (4-fluorophenyl) -4-oxo-butyl or 4-oxo-4-phenylbutyl. Especially preferred salts are those in which the azoniabicyclo group is substituted on the nitrogen atom with 3-phenoxypropyl, 2-phenoxyethyl, 3-phenylallyl, phenethyl, 3-phenylpropyl, 3- (3-hydroxyphenoxy) propyl, 3- (4- fluorophenoxy) propyl, 3-thien-2-ylpropyl, 4-oxo-4-thien-2-ylbutyl, 2-benzyloxyethyl, 3-o-tolyloxypropyl, 3- (3-cyanophenoxy) propyl, 3- (methylphenylamino) propyl, 3- (2,4-difluorophenoxy) propyl, 3- (4-methoxyifexy) propyl, 3- (2,4-difluorophenoxy) propyl, 3- (2-chlorophenoxy) propyl, 3- benzo [1,3] dioxol-5-yloxy) propyl. Examples of especially preferred salts are those in which the azoniabicyclo group is substituted on the nitrogen atom with a 3-phenoxypropyl, 2-phenoxyethyl, 3-phenylallyl, phenethyl, 3-phenylpropyl, 3- (3-hydroxyphenoxy) propyl group, 3- (4-fluorophenyl) propyl, 3-thien-2-ylpropyl.

Further preferred compounds of formula (I) are those wherein R 4 represents a phenyl, 2-thienyl, 3-thienyl, 2-furyl or 3-furyl group. R11 is preferably a hydrogen or halogen atom or an unsubstituted lower alkyl group such as methyl or ethyl. Most preferably R 11 is a hydrogen atom. As a consequence, for example, R 4 may represent an unsubstituted, 2-thienyl or 2-furyl phenyl group. Alternatively, R 4 may represent an unsubstituted phenyl or 2-thienyl group. Preferably, R 5 represents a benzyl, phenethyl, cyclopentyl, cyclohexyl, C 2-5 alkyl, C 2-5 alkenyl or C 2-5 alkynyl group, particularly a cyclopentyl, cyclohexyl, pentyl, allyl, vinyl, propynyl, phenethyl or benzyl. Alternatively, R 5 represents a benzyl, cyclopentyl, cyclohexyl, C 2-5 alkyl, C 2-5 alkenyl, C 2-5 alkynyl, particularly a cyclopentyl, cyclohexyl, pentyl, allyl, vinyl, propynyl or benzyl group. The asymmetric alpha carbon of the ester group, which is substituted with R4, R5 and R6 may have R or S configuration.

Preferred compounds of formula (I) are those wherein the group -O-C0-C (R4) (R5) (R6) is selected from 2-cyclopentyl-2-hydroxy-2-thien-2-ylacetoxy, 2,3-diphenylpropionyloxy; 2-hydroxymethyl-2,3-diphenylpropionyloxy; 2-hydroxy-2,3-diphenylpropionyloxy; 2-hydroxy-3-phenyl-2-thien-2-ylpropionyloxy; 2-hydroxy-2-thien-2-ylpent-4-enoyloxy; 2-hydroxy-2-thien-2-yl-heptanoyloxy; 2-hydroxy-2-thien-2-ylpent-3-ynoyloxy; 2-hydroxy-2-thien-2-ylbut-3-enoxyloxy; 2-cyclopentyl-2-fur-2-yl-2-hydroxyacetoxy; 2-cyclohexyl-2-hydroxy-2-phenylacetoxy; 2-cyclohexyl-2-fur-2-yl-2-hydroxyacetoxy; 2-cyclopentyl-2-hydroxy-2-phenylacetoxy; 2-cyclohexyl-2-hydroxy-2-thien-2-ylacetoxy and 2-hydroxy-4-phenyl-17β-pyridyl-2-thien-2-ylbutanoyloxy. Examples of the group -O-CO-C (R 4) (R 5) (R 6) are 2-cyclopentyl-2-hydroxy-2-thien-2-ylacetoxy; 2,3-diphenylpropionyloxy; 2-hydroxymethyl-2,3-diphenyl-propionyloxy; 2-hydroxy-2,3-diphenylpropionyloxy] -2-hydroxy-3-phenyl-2-thien-2-ylpropionyloxy] -2-hydroxy-2-thien-2-ylpent-4-enoyloxy; 2-hydroxy-2-thien-2-yl-hepatanoyloxy] -2-thien-2-ylpent-3-yloxy] -2-hydroxy-2-thien-2-ylbut-3-enoyloxy; 2-cyclopentyl-2-fur-2-yl-2-hydroxyacetoxy; 2-cyclohexyl-2-hydroxy-2-phenylacetoxy and 2-cyclohexyl-2-fur-2-yl-2-hydroxyacetoxy.

In the most preferred embodiments of the invention p is 2, the azoniabicyclo [2.2.2] ring is substituted at the 3-position; and this substituted carbon atom has the (R) configuration.

The following compounds are intended to illustrate, but not limit, the domain of the present invention:

(3 R) -3- (2,3-Diphenylpropionyloxy) -1- (3-phenoxypropyl) -1-azoniabicyclo [2.2.2] octane trifluoroacetate

(3 R) -3- (2,3-diphenylpropionyloxy) -1- (3-thien-2-ylpropyl) -1-azoniabicyclo [2.2.2] octane trifluoroacetate

(3R) -3 - [(2R) -2-hydroxymethyl-2,3-diphenylpropionyloxy] -1- (3-thien-2-ylpropyl) -1-azonia-bicyclo [2.2.2] octane trifluoroacetate (diastereomer 1)

(3R) -3 - [(2R) -2-hydroxymethyl-2,3-diphenylpropionyloxy] -1-phenethyl-1-azoniabicyclo [2.2.2] octane trifluoroacetate (diastereomer 1)

(3R) -3 - [(2 *) -2-hydroxymethyl-18α -13β3919 2,3-diphenylpropionyloxy) -1- (3-thien-2-ylpropyl) -1-azonia-bicyclo [2.2.2] octane trifluoroacetate (diastereomer 2)

(3R) -3 - [(2R) -2-hydroxymethyl-2,3-diphenylpropionyloxy] -1-phenethyl-1-azoniabicyclo [2.2.2] octane (diastereomer 2) trifluoroacetate

(3R) -3 - [(2R) -2-hydroxymethyl-2,3-diphenylpropionyloxy] -1- (3-phenoxypropyl) -1-azoniabicyclo [2.2.2] octane bromide (diastereomer 1)

(3R) -3 - [(2R) -2-hydroxymethyl-2,3-diphenylpropionyloxy] -1- (2-phenoxypropyl) -1-azoniabicyclo [2.2.2] octane bromide (diastereomer 1)

(3R) -3 - [(2R) -2-hydroxymethyl-2,3-diphenylpropionyloxy] -1- (3-phenoxypropyl) -1-azoniabicyclo [2.2.2] octane trifluoroacetate (diastereomer 2)

(3R) -3 - [(2R) -2-Hydroxymethyl-2,3-diphenylpropionyloxy] -1- (2-phenoxypropyl) -1-azoniabicyclo [2.2.1] 2 . 2] octane (diastereomer 2)

(3R) -3- (2-Hydroxymethyl-3-phenyl-2-thien-2-ylpropionyloxy] -1- (3-phenoxypropyl) -1-azonia-bicyclo [2.2.2] octane trifluoroacetate

(3R) -3- (2-hydroxymethyl-3-phenyl-2-thien-2-ylpropionyloxy] -1- (3-thien-2-ylpropyl) -1-azoniabicyclo [2.2.2] octane trifluoroacetate

(3R) -3- (2-Hydroxy-2-thien-2-ylpent-4-ennoyloxy] -1- (3-phenoxypropyl) -1-azoniabicyclo [2.2.2] octane trifluoroacetate - (2-hydroxy-2-thien-2-ylpent-4-ennoyloxy] -1- (3-thien-2-ylpropyl) -1-azoniabicyclo [2.2.2] octane

(3 R) -3- (2-phenoxypropyl) -1-azoniabicyclo [2.2.2] octane trifluoroacetate (3R) -3- (2-hydroxy-2-thien- -3- (2-hydroxy-2-thien-2-yl-heptanoyloxy] -1- (3-phenoxypropyl) -1-azoniabicyclo [2.2.2] octane

(3R) -3- (2-Hydroxy-2-thien-2-yl-heptanoyloxy] -1- (3-thien-2-ylpropyl) -1-azoniabicyclo [2.2.2] octane trifluoroacetate

(3R) -3- (2-Hydroxy-2-thien-2-ylpent-3-yloxy] -1- (3-phenoxypropyl) -1-azoniabicyclo [2.2.2] octane trifluoroacetate

(3R) -3- (2-Hydroxy-2-thien-2-ylpent-3-ynoyloxy) -1- (3-thien-2-ylpropyl) -1-azoniabicyclo [2.2.2] octane trifluoroacetate

(3R) -3- (2-Hydroxy-2-thien-2-ylbut-3-ynoyloxy) -1- (3-phenoxypropyl) -1-azoniabicyclo [2.2.2] octane trifluoroacetate

(3R) -3- (2-hydroxy-2-thien-2-ylbut-3-ynoyloxy) -1- (3-thien-2-ylpropyl) -1-azoniabicyclo [2.2.2] octane trifluoroacetate

(3R) -3 - [(2S) -2-Cyclopentyl-2-hydroxy-2-thien-2-ylacetoxy] -1- (3-phenoxypropyl) -1-azoniabicyclo [2.2.2] octane bromide

(3R) -3 - [(2S) -2-cyclopentyl-2-hydroxy-2-thien-2-ylacetoxy] -1- (3-thien-2-ylpropyl) -1-azoniabicyclo [2.2.2] octane

(3R) -3 - [(2S) -2-Cyclopentyl-2-hydroxy-2-thien-2-ylacetoxy] -1- (2-phenoxyethyl) -1-azoniabicyclo [2.2.2] octane bromide

(3R) -3 - [(2S) -2-Cyclopentyl-2 - [(eth-3-propenyl) -1-phenethyl-1-azoniabicyclo [2.2.2] octane trifluoroacetate

(3R) -3 - [(2S) -2-cyclopentyl-2-hydroxy-2-thien-2-ylacetoxy] -1- (3-phenylpropyl) -1-azonia-bicyclo [2.2.2] octane trifluoroacetate

(3R) -3 - [(2S) -2-cyclopentyl-2-hydroxy-2-thien-2-ylacetoxy] -1- (3-phenylalyl) -1-azonia-bicyclo [2.2.2] octane trifluoroacetate

(3R) -3 - [(2S) -2-cyclopentyl-2-hydroxy-2-thien-2-ylacetoxy] -1- [3- (4-fluorophenoxy) propyl] -1-azoniabicyclo [2.2.2 ]octane

(3R) -3 - [(2S) -2-cyclopentyl-2-hydroxy-2-thien-2-ylacetoxy] -1- (4-oxo-4-thien-2-ylbutyl) -1-azoniabicyclo [ 2.2.2] octane

(3R) -3 - [(2S) -2-cyclopentyl-2-hydroxy-2-thien-2-ylacetoxy] -1- [4- (4-fluorophenyl) -4-oxobutyl] -1- azoniabicyclo [2.2.2] octane

(3R) -3 - [(2S) -2-cyclopentyl-2-hydroxy-2-thien-2-ylacetoxy] -1- [3- (3-hydroxyphenoxy) propyl] -1-azoniabicyclo [2.2.2 ]octane

1- (2-Benzyloxyethyl) - (3R) -3 - [(2S) -2-cyclopentyl-2-hydroxy-2-thien-2-ylacetoxy] -1-azonia-bicyclo [2.2.2] octane trifluoroacetate

(3R) -3 - [(2S) -2-cyclopentyl-2-hydroxy-2-thien-2-ylacetoxy] -1- (3-o-tolyloxypropyl) -1-azoniabicyclo [2.2.2] octane trifluoroacetate

1- [3- (3-Cyanophenoxy) propyl] - (3R) -3 - [(2S) -2-cyclopentyl-2-hydroxy-2-thien-2-ylacetoxy] -1-azoniabicyclo [2.2.2 ]octane

(3R) -3 - [(2S) -2-Cyclopentyl-2-2β, 13β] -13β-hydroxy-2-thien-2-ylacetoxy] -1- [3- (naphthalen-1-yloxy) propyl] -1-azoniabicyclo [2.2.2] octane

(3R) -3 - [(2S) -2-Cyclopentyl-2-hydroxy-2-thien-2-ylacetoxy] -1- [3- (methylphenylamino) propyl] -1-azoniabicyclo [2.2.2] octane trifluoroacetate

(3R) -3 - [(2S) -2-cyclopentyl-2-hydroxy-2-thien-2-ylacetoxy] -1- (3-phenylsulfanylpropyl) -1-azoniabicyclo [2.2.2] octane trifluoroacetate

(3R) -3 - [(2S) -2-Cyclopentyl-2-hydroxy-2-thien-2-ylacetoxy] -1- (4-oxo-4-phenylbutyl) -1-azoniabicyclo [2.2.2] octane

(3R) -3 - [(2S) -2-Cyclopentyl-2-hydroxy-2-thien-2-ylacetoxy] -1- [3- (2,4,6-trimethylphenoxy) pro-pyl] -1 -azoniabicyclo [2.2.2] octane

1- [3- (2-Chlorophenoxy) propyl] - (3R) -3 - [(2S) -2-cyclopentyl-2-hydroxy-2-thien-2-ylacetoxy] -1-azoniabicyclo [2.2.1] 2] octane

(3R) -3 - [(2S) -2-cyclopentyl-2-hydroxy-2-thien-2-ylacetoxy] -1- [3- (3-trifluoromethylphenoxy) propyl] -1-azoniabicyclo [2.2.1] 2] octane

1- [3- (biphenyl-4-yloxy) propyl] - (3R) -3 - [(2S) -2-cyclopentyl-2-hydroxy-2-thien-2-ylacetoxy] -1-azoniabicyclo [2.2.2] octane

(3R) -3 - [(2S) -2-cyclopentyl-2-hydroxy-2-thien-2-ylacetoxy] -1- [3- (2,4-difluorophenoxy) pro-pyl] -1-azoniabicyclo [2.2.2] octane

(3R) -3 - [(2S) -2-cyclopentyl-2-hydroxy-2-thien-2-ylacetoxy] -1- [3- (4-methoxyphenoxy) propyl] -1-azoniabicyclo [2.2.2 ]octane

(3R) -3 - [(2S) -2-Cyclopentyl-2-methyl-2-thia-2-ylacetoxy] -1- [3- (5,6,7,8-tetrahydronaphth- leno-2-yloxy) propyl] -1-azoniabicyclo [2.2.2] octane

1- [3- (Benzo [1,3] dioxol-5-yloxy) propyl] - (3R) -3 - [(2S) -2-cyclopentyl-2-hydroxy-2-thien-2-ylacetoxy ] -1-azoniabicyclo [2.2.2] octane

1- [3- (2-carbamoylphenoxy) propyl] - (3R) -3 - [(2S) -2-cyclopentyl-2-hydroxy-2-thien-2-ylacetoxy] -1-azoniabicyclo [2.2.2 ]octane

(3R) -3 - [(2S) -2-cyclopentyl-2-hydroxy-2-thien-2-ylacetoxy] - [3- (3-dimethylaminophenoxy) propyl] -1-azoniabicyclo [2.2.2] octane trifluoroacetate

1- [3- (4-Acetylaminophenoxy) propyl] - (3R) -3 - [(2S) -2-cyclopentyl-2-hydroxy-2-thien-2-ylacetoxy] -1-azoniabicyclo [2.2.1] 2] octane

(3R) -3 - [(2S) -2-cyclopentyl-2-hydroxy-2-thien-2-ylacetoxy] -1- [3- (4-methoxycarbonylphenoxy) propyl] -1-azoniabicyclo [2.2.2 ]octane

(3R) -3 - [(2S) -2-cyclopentyl-2-hydroxy-2-thien-2-ylacetoxy] -1- [3- (4-nitrophenoxy) propyl] -1-azoniabicyclo [2.2.2 ]octane

(3R) -3 - [(2S) -2-Cyclopentyl-2-hydroxy-2-thien-2-ylacetoxy] -1- [3- (4-hydroxymethylphenoxy) propyl] -1-azoniabicyclo [2.2.1] 2] octane

(3R) -3 - [(2R) -2-Cyclopentyl-2-hydroxy-2-thien-2-ylacetoxy] -1- [3- (3-phenoxypropyl) -1-azoniabicyclo [2.2.2] octane

(3R) -3 - [(2R) -2-cyclopentyl-2-hydroxy-2-thien-2-ylacetoxy] -1- (3-thien-2-ylpropyl) -1-azoniabicyclo [2.2.2] octane

(3R) -3 - [(2R) -2-Cyclopentyl-2-2β-β3,339,9hydroxy-2-thien-2-ylacetoxy] -1- (2-phenoxyethyl) -1-azoniabicyclo [2.2.2] octane

(3R) -3 - [(2R) -2-Cyclopentyl-2-hydroxy-2-thien-2-ylacetoxy] -1-phenethyl-1-azoniabicyclo [2.2.2] octane trifluoroacetate

(3R) -3 - [(2R) -2-cyclopentyl-2-hydroxy-2-thien-2-ylacetoxy] -1- (3-phenylpropyl) -1-azonia-bicyclo [2.2.2] octane trifluoroacetate

(3R) -3 - [(2R) -2-cyclopentyl-2-hydroxy-2-thien-2-ylacetoxy] -1- (3-phenylalyl) -1-azonia-bicyclo [2.2.2] octane trifluoroacetate

(3R) -3 - [(2R) -2-cyclopentyl-2-hydroxy-2-thien-2-ylacetoxy] -1- [3- (4-fluorophenoxy) propyl] -1-azoniabicyclo [2.2.2 ]octane

(3R) -3 - [(2S) -2-cyclopentyl-2-fur-2-yl-2-hydroxyacetoxy] -1- (3-phenoxypropyl) -1-azonia-bicyclo [2.2.2] octane trifluoroacetate

(3R) -3 - [(2S) -2-cyclopentyl-2-fur-2-yl-2-hydroxyacetoxy] -1- (3-thien-2-ylpropyl) -1-azonia-bicyclo [2.2.1] 2] octane

(3R) -3 - [(2S) -2-Cyclopentyl-2-fur-2-yl-2-hydroxyacetoxy] -1-phenethyl-1-azoniabicyclo [2.2.2] octane trifluoroacetate

(3R) -3 - [(2S) -2-cyclopentyl-2-fur-2-yl-2-hydroxyacetoxy] -1- (3-phenylpropyl) -1-azonia-bicyclo [2.2.2] octane trifluoroacetate

(3R) -3 - [(2R) -2-cyclopentyl-2-fur-2-yl-2-hydroxyacetoxy] -1- (3-phenoxypropyl) -1-azonia-bicyclo [2.2.2] octane trifluoroacetate

(3R) -3 - [(2R) -2-cyclopentyl-2-fur-2-yl-2-hydroxyacetoxy] -1- (3-thien-2-ylpropyl) -1-azonia bicyclo [2.2.2] octane

(3R) -3 - [(2R) -2-Cyclopentyl-fur-2-yl-2-hydroxyacetoxy] -1-phenethyl-1-azoniabicyclo [2.2.2] octane trifluoroacetate

(3R) -3 - [(2R) -2-cyclopentyl-fur-2-yl-2-hydroxyacetoxy] -1- (3-phenylpropyl) -1-azonia-bicyclo [2.2.2] octane trifluoroacetate

(3R) -3 - [(2R) -2-cyclohexylhydroxy-2-phenylacetoxy] -1- (3-phenoxypropyl) -1-azonia-bicyclo [2.2.2] octane trifluoroacetate

(3R) -3 - [(2R) -2-cyclohexylhydroxy-2-phenylacetoxy] -1- (3-thien-2-ylpropyl) -1-azonia-bicyclo [2.2.2] octane trifluoroacetate

(3R) -3 - [(2R) -2-cyclohexylhydroxy-2-phenylacetoxy] -1-phenethyl-1-azoniabicyclo [2.2.2] octane trifluoroacetate

(3R) -3 - [(2S) -2-cyclohexylhydroxy-2-phenylacetoxy] -1- (3-phenoxypropyl) -1-azonia-bicyclo [2.2.2] octane trifluoroacetate

(3R) -3 - [(2S) -2-cyclohexylhydroxy-2-phenylacetoxy] -1- (3-thien-2-ylpropyl) -1-azonia-bicyclo [2.2.2] octane trifluoroacetate

(3R) -3 - [(2S) -2-Cyclohexylhydroxy-2-phenylacetoxy] -1-phenethyl-1-azoniabicyclo [2.2.2] octane trifluoroacetate

(3R) -3 - [(2S) -2-cyclohexyl-fur-2-yl-2-hydroxyacetoxy] -1- (3-phenoxypropyl) -1-azonia-bicyclo [2.2.2] octane trifluoroacetate

(3R) -3 - [(2S) -2-cyclohexyl-25α -13β3919 fur-2-yl-2-hydroxyacetoxy] -1- (3-thien-2-ylpropyl) -1-azonia bicyclo [2.2 .2] octane

(3R) -3 - [(2S) -2-Cyclohexyl-fur-2-yl-2-hydroxyacetoxy] -1-phenethyl-1-azoniabicyclo [2.2.2] octane trifluoroacetate

(3R) -3 - [(2S) -2-cyclohexyl-fur-2-yl-2-hydroxyacetoxy] -1- (3-phenylpropyl) -1-azonia-bicyclo [2.2.2] octane trifluoroacetate

(3R) -3 - [(2R) -2-cyclohexyl-fur-2-yl-2-hydroxyacetoxy] -1- (3-phenoxypropyl) -1-azonia-bicyclo [2.2.2] octane trifluoroacetate

(3R) -3 - [(2R) -2-cyclohexyl-fur-2-yl-2-hydroxyacetoxy] -1- (3-thien-2-ylpropyl) -1-azonia bicyclo [2.2.2 ]octane

(3 R) -3 - [(2 R) -2-Cyclohexyl-fur-2-yl-2-hydroxyacetoxy] -1-phenethyl-1-azoniabicyclo [2.2.2] octane trifluoroacetate

(3R) -3 - [(2R) -2-cyclohexyl-fur-2-yl-2-hydroxyacetoxy] -1- (3-phenylpropyl) -1-azonia-bicyclo [2.2.2] octane trifluoroacetate

(3R) -3 - [(2R) -2-cyclopentyl-hydroxy-2-phenylacetoxy] -1- (3-phenoxypropyl) -1-azonia-bicyclo [2.2.2] octane trifluoroacetate

(3R) -3 - [(2R) -2-cyclopentyl-hydroxy-2-phenylacetoxy] -1-phenethyl-1-azoniabicyclo [2.2.2] octane trifluoroacetate

(3R) -3 - [(2R) -2-cyclopentylhydroxy-2-phenylacetoxy] -1- (3-phenylsulfanylpropyl) -1-azoniabicyclo [2.2.2] octane trifluoroacetate

(3R) -3 - [(2S) -2-cyclopentyl] -β-hydroxy-2-phenylacetoxy] -1- (3-phenoxypropyl) -1-azonia-bicyclo [2.2.2] octane trifluoroacetate

(3R) -3 - [(2S) -2-Cyclopentyl-hydroxy-2-phenylacetoxy] -1-phenethyl-1-azoniabicyclo [2.2.2] octane trifluoroacetate

(3R) -3 - [(2S) -2-cyclopentyl-hydroxy-2-phenylacetoxy] -1- (3-phenylsulfanylpropyl) -1-azoniabicyclo [2.2.2] octane trifluoroacetate

(3R) -3 - [(2S) -2-cyclohexylhydroxy-2-thien-2-ylacetoxy] -1- (3-phenoxypropyl) -1-azonia-bicyclo [2.2.2] octane trifluoroacetate

(3R) -3 - [(2S) -2-Cyclohexylhydroxy-2-thien-2-ylacetoxy] -1-phenethyl-1-azoniabicyclo [2.2.2] octane trifluoroacetate

1- [3- (3-Cyanophenoxy) propyl] -3 - [(2S) -2-cyclohexyl-2-hydroxy-2-thien-2-ylacetoxy] -azoniabicyclo [2.2.2] octane

(3R) -3 - [(2R) -2-cyclohexylhydroxy-2-thien-2-ylacetoxy] -1- (3-phenoxypropyl) -1-azonia-bicyclo [2.2.2] octane trifluoroacetate

(3R) -3 - [(2R) -2-cyclohexylhydroxy-2-thien-2-ylacetoxy] -1-phenethyl-1-azoniabicyclo [2.2.2] octane trifluoroacetate

1- [3- (3-Cyanophenoxy) propyl (3R) -3 - [(2R) -2-cyclohexyl-2-hydroxy-2-thien-2-ylacetoxy] -azoniabicyclo [2.2.2] octane trifluoroacetate

(3R) -3- (2-Hydroxy-4-phenyl-thien-2-ylbutanoyloxy) -1- (3-phenoxypropyl) -1-azoniabicyclo [2.2.2] octane trifluoroacetate

(3S) -3 - [(2S) -2-Cyclopentyl-2-hydroxy] -2-thien-2-ylacetoxy] -1- (3-phenoxypropyl) -1-azoniabicyclo [2.2.2] octane

(3S) -3 - [(2S) -2-Cyclopentyl-2-hydroxy-2-thien-2-ylacetoxy] -1- (3-thien-2-ylpropyl) -1-azoniabicyclo [2.2.1] 2] octane

(3S) -3 - [(2S) -2-Cyclopentyl-2-hydroxy-2-thien-2-ylacetoxy] -1- (3-phenylpropyl) -1-azonia-bicyclo [2.2.1] 2] octane

4 - [(2R) -2-Cyclohexyl-2-hydroxy-2-phenylacetoxy] -1- (3-thien-2-ylpropyl) -1-azonia-bicyclo [2.2.2] octane trifluoroacetate

4 - [(2R) -2-cyclohexyl-2-hydroxy-2-phenylacetoxy] -1- (3-phenoxypropyl) -1-azonia-bicyclo [2.2.2] octane trifluoroacetate: not assigned; both (2R) and (2S) isomers of the foregoing compounds can be produced. The present invention also provides processes for preparing compounds of formula (I). Quaternary ammonium derivatives of general formula (I) may be prepared by reaction of an alkylating agent of general formula (II) with compounds of general formula (III). In the formulas (I), (II) and (III), R 1, R 2, R 3, B, A, X ', R 4, R 5, R 6, n, m and p are as defined above. ΡΕ1353919 28

c * >

In formula (II), W represents any suitable leaving group, such as the group X as defined above. Preferably, W represents an X group.

This alkylation reaction can be carried out by two experimental procedures, a), and b) which are described above. In particular, method b) provides a novel experimental process using solid phase extraction methodologies, which allows the parallel preparation of various compounds. Methods a) and b) are described in the experimental section. If W represents a group other than X, the quaternary ammonium salt of formula (I) is produced from the product of method (a) or (b) by performing an exchange reaction according to standard methods to replace the anion W "With the desired anion X".

Compounds of formula (II) which are not commercially available were prepared by synthesis of 29 ΡΕ 1355919 according to standard methods. For example, compounds wherein n = 0 and A = -O-, -S- or -NR9-, wherein R9 is as defined above, were obtained by reacting the corresponding aromatic derivative or its potassium salt with a alkylating agent of the general formula Y- (CH 2) m X, wherein X may be a halogen and Y may be a halogen or a sulfonate ester. In other examples, the compounds of general formula (II), wherein η> 1 were synthesized from the corresponding alcohol of formula (IV) by known methods

wherein R 1, R 2, R 3, n, m and A are as defined above.

The compounds of general formula (III) may be prepared by different methods. These procedures are illustrated in the following schemes and detailed in the experimental section. Method c)

Compounds of formula (III) may be synthesized by transesterification of a compound of formula (V) with a compound of formula (VI). 30 ΡΕ1353919

wherein the formulas R4, R5, R6 and p are as defined above and L represents a leaving group. For example, L may be a chlorine atom, an imidazol-1-yl group, or a group -OR14 in which R14 represents a linear or branched chain, unsubstituted or substituted alkyl group or a -COR15 group wherein R15 represents -COCR 4 R 5 R 6. Typically L is -OR 14 wherein R 14 is methyl, ethyl or propyl, or L is an imidazol-1-yl group.

Intermediates of formula (VI) may be prepared by standard methods described in the literature, for example, as in FR 2012964. Method d)

Compounds of formula (III) wherein R 6 is a hydroxide group and p, R 4 and R 5 are as described above may also be prepared from glyoxalate esters of general formula (VII) by reaction with the corresponding Grignard reagent. 31 ΡΕ1353919

Compounds of formula (VII) may be prepared by standard methods described in the literature (WO 01/04118; WO 92/04346). Method e)

Compounds of formula (III) wherein R 6 is a -CH 2 OH group, and R 4 and R 5 are as described above may also be prepared from the corresponding compound of formula (III), wherein R 6 is a hydrogen atom, by reaction with formaldehyde under basic conditions. (Organic Synthesis Collective Volumes, VII, 271-274, (1990); WO 93/06098)

32 ΡΕ1353919

As will be described in the experimental part, the diastereomers of the compounds of formula (III) may be separated by conventional methods, for example, by column chromatography or by crystallization.

The following compounds are compounds of general formula (III) which have not been described above:

compounds of formula III R4

wherein p, R4, R5 and R6 are as defined above, the substituent being on the azabicyclo group in the 3 or 4 position and when in position 3 this substituted carbon has an enantiomerically pure R or S configuration, provided that when R4 is a 3-thienyl group and R 5 is cyclohexyl, R 6 is not a hydroxide group. The substituent on the azabicyclo group is preferably in the 3-position and may have a R or S configuration. The carbon substituted with R 4, R 6 and R 6 may have R or S configuration. The compound may be a single isomer. 33 ΡΕ1353919

Examples of the novel compounds of formula (III) include: (2S) -2-Cyclopentyl-2-fur-2-yl-2-hydroxyacetic acid (3R) -1-azabicyclo [2.2.2] oct- ([Î ±] 22d = + 19.7Â ° (c = 1, CHCl3)). (2R) -2-Cyclopentyl-2-fur-2-yl-2-hydroxyacetic acid (3R) -1-azabicyclo [2.2.2] oct-3- (c = 1, CHCl3)). (2S) -2-Cyclohexyl-2-fur-2-yl-2-hydroxyacetic acid (3R) -1-azabicyclo [2.2.2] oct-3- , 1 ° (c = 1, CHCl3)). (2R) -2-Cyclohexyl-2-fur-2-yl-2-hydroxyacetic acid (3R) -1-azabicyclo [2.2.2] oct- 5 ° (c = 1, CHCl3)). (2 R) -2-Cyclohexyl-2-hydroxy-2-phenylacetic acid 1-azabicyclo [2.2.2] oct-4-yl ester ([Î ±] 22d = -27.6Â ° (c = 1, CHCl3 )). (2 S) -2-Cyclopentyl-2-fur-2-yl-2-hydroxyacetic acid (3 R) -1-azabicyclo [2.2.2] oct- (C = 1, CHCl3)). (2R) -2-Cyclopentyl-2-fur-2-yl-2-hydroxyacetic acid (3R) -1-azabicyclo [2.2.2] oct-3- (c = 1, CHCl3)). (2S) -2-Cyclohexyl-2-fur-2-yl-2-hydroxyacetic acid (3R) -1-azabicyclo [2.2.2] oct- 1 (c = 1, CHCl3)). 1-azabicyclo [2.2.2] oct-3-yl ester (2R) -2-cyclohexyl-2-fur-2-yl-2-hydroxyacetic acid ([Î ±] D = -23.5 ° (c = 1, CHCl3)).

The compounds of formula (V) may be: 4-Hydroxy-1-azabicyclo [2.2.1] heptane, described in WO 93/15080 4-Hydroxy-1-azabicyclo [2.2.1] octane, described in Grob, CA et al. Helv. Chim. (1958), 41, 1184-1190 (3R) -3-Hydroxy-1-azabicyclo [2.2.2] octane or (3R) -3-hydroxy-1-azabicyclo [2.2.2] octane, described in Ringdahl, R. Acta Pharm. Suec. (1979), 16, 281-283 and commercially available from CU Chemie Uetikon GmbH.

The following examples are intended to illustrate, but not limit, the experimental procedures which have been described above.

The structures of the compounds prepared were confirmed by 1 H-NMR and MS. NMR spectra were recorded using a Varian 300 MHz equipment and the chemical shifts are expressed in parts per million (δ) relative to the internal tetramethylsilane reference. Its purity was determined by HPLC using reverse phase chromatography on a Waters apparatus, with values greater than 95% being obtained. Molecular ions were obtained using a PERKIN-ELMER 241 MC Polarimeter. ΡΕ1353919 35 -A-

Example 13

Preparation of (3R) -3- (2-hydroxy-2-thien-1-ylpent-4-enoyloxy) -1- (3-phenoxypropyl) -1-azoniabicyclo [2.2.2] octane bromide 250 mg 81 mmol) of the 2-hydroxy-2-thien-2-ylpent-4-enoic acid (3R) -1-azabicyclo [2.2.2] oct-3-yl ester, intermediate 1-3, was dissolved in 5 ml of acetonitrile and 7.5 ml of chloroform. To this solution was added 0.63 mL (4.1 mmol) of phenoxypropyl bromide. After stirring 48 h at room temperature under N 2 atmosphere, the solvents were evaporated. Ether was added and the mixture was stirred. The solid obtained was filtered and washed several times with ether. The yield was 0.3 g (71%) of the title compound as a mixture of diastereomers; mp: 157 ° C. 1 H-NMR (DMSOd 6): δ 1.70-2.05 (m, 4H), 2.05-2.35 (m, 3H), 2.70-2.83 (m, 1H), 2. , M.p. 90-3.02 (m, 1H), 3.25-3.60 (m, 7H), 3.82-3.97 (m, 1H), 3.97-4.10 (m, 2H) (M, 1H), 6.50 (d, 1H, OH), 6.90-7.05 (m, 4H) , 7.10-7.20 (m, 1H), 7.27-7.35 (m, 2H), 7.45 (m, 1H). MS: [M-Br] +: 442. ΡΕ1353919 Method -b-

Example 35

Preparation of (3R) -3 - [(2S) -2-cyclopentyl-2-hydroxy-2-thien-2-ylacetoxy] -1- [3- (naphthalen-1-yloxy) propyl] -1-azoniabicyclo (2S) -2-Cyclopentyl-2-hydroxy-2-oxobicyclo [2.2.2] octane 20 mg (0.06 mmol) thien-2-ylacetic acid, intermediate (intermediate I-15a), was dissolved in 1 ml of DMSO. To this solution was added 66 mg (0.30 mmol) of 3- (naphthalen-1-yloxy) propyl chloride. After stirring overnight at room temperature, the mixture was purified by solid phase extraction with a Cation Exchange Mega Bond Elut cartridge, previously conditioned to pH = 7.5 with 0.1 N NaH 2 PO 4 buffer. The reaction mixture was applied to the cartridge and washed first with 2 ml of DMSO and then three times with 5 ml of CH 3 CN, rinsing all starting materials. The ammonium derivative was eluted with 5 ml of 0.03 M TFA solution in CH 3 CN: CHCl 3 (2: 1). This solution was neutralized with 300 mg of poly (4-vinylpyridine), filtered and evaporated to dryness. The yield was 10 mg (26%) of the title compound. 1 H-NMR (DMSO-d 6): δ 1.30-1.65 (m, 1), 1.80-2.10 (m, 4H), 2.20-2.37 (m, 3H), 2.75 (M, 7H), 3.90-4.05 (m, 1H), 4.15-4.30 (m, 2H), 5 (M, 1H), 6.15 (s, 1H, OH), 6.95-7.05 (m, 2H), 7.15-7.20 (m, 1H) , 7.40-7.60 (m, 5H), 7.85-7.95 (m, 1H), 8.20-8.25 (m, 1H) MS: [M-CF3 COO] +: 520

The spatial configurations of the compounds of formula (III) have been deduced from the corresponding acid configurations thereof. These were determined either by comparing the values of [a] obtained with the values described in the literature or by applying the Circular Dichroism (CD) technique.

Since the CD curve of (2S) -2-cyclohexyl-2-hydroxy-2-phenylacetic acid is known (A. Tambuté and A. Collet, Bulletin de la Societe Chimique de France, 1984, No. 1 -2, pages 1177 to 1182) and all evaluated acids are structurally very similar to (2S) -2-cyclohexyl-2-hydroxy-2-phenylacetic acid, it can be assumed that the relative positions of the substituents aryl, cycloalkyl, carboxyl and hydroxyl groups can be identified by comparison with the respective Δε values. The resulting configurations were expressed as R or S according to the Cahn-Ingol-Prelog system. (system TABLE 1)

CD spectra curves were recorded with a Jasco-720 spectrophotometer (Software J-700) from 0.43 mM MeOH solutions of the samples in 1 mm cells at 25 ° C. ΡΕ1353919 38 TABLE 1

Compound Circular Dichroism [CX] 22d λ (nm) Δε (M 1cm x) Configuration (+) - Cyclohexyl-2 + 23,1 ° (c = 224 + 12.1 g, hydroxyl 2-phenylacetic acid 1, 4-EtOH) (-) - Cyclohexyl-2-23,6o (c-224 -11.7 R hydroxy-2-phenylacetic acid 1,4, EtOH) (-) - Cyclopentyl-2- (+) - cyclopentyl-2- + 6,63 ° (c = 1.233 + 4.18 R -hydroxy-2-phenylacetic acid MeOH) phenylacetic acid (1 EtOH) (-) - Cyclopentyl-2-hydroxy-2-thien-1-ylacetic acid (EtOH) (+) - cyclopentyl-2-hydroxy-2-hydroxy-2-thienyl] , 95 (c = 1, 230 + 7.64 s fur-2-yl-2-hydroxyacetic acid EtOH) (-) - Cyclopentyl-2-O- -2-yl-2-hydroxyacetic acid 1, EtOH) (+) - Cyclohexyl-2 + 40.9 ° (c = 1, 230 + 10, 9S-fur-2-yl-2-hydroxyacetic acid EtOH) (-) - Cyclohexyl-2-yl) - " (a) A. Tambuté and A. Collet, Bulletin de la Societe Chimique de France, (1984), No. 1-2, et al. pages 1177 to 1182: S-configuration assigned with [Î ±] 20d - + 25.2Â ° (C = 1.4, EtOH), Δε - +12.9 Mn cnT1 (λ = 225 nm) M. Mitsuya et al. al .; Bioorg. Med. Chem., (1999) Vol. 2555-2567: R configuration assigned with [Î ±] 20D = -1.9Â ° (C = 3, MeOH) c) E. Atkinson et al., J. Med. Chem., (1977), Vol. 20, No. 12, No. 12, 1612-1617. The values for [a] were given (unassigned conflation); c, 1 and c, 2: + 51.3 ° and -51.0 ° (rotations observed at 350 nm (c = 2-5%, MeOH)) ΡΕ1353919 39 40 ΡΕ1353919 -c-

Methyl ester derivatives of general formula (VI) were prepared by standard methods described in the literature or following the procedures described in the examples: intermediates 1-9, 1-10, 1-11, 1-12, 1-13.

Intermediate 1-1

Preparation of 2-hydroxy-2-thien-2-yl-heptanoic acid (3R) -1-azabicyclo [2.2.2] oct-3- thien-2-yl-heptanoic acid (intermediate 1-9) (0.011 mol) was dissolved in 70 ml of toluene. To this solution was added 1.63 g (0.0128 mol) of (3R) -3-hydroxy-1-azabicyclo [2.2.2] octane and 0.18 g (0.00445 mol) of HNa (60% of dispersion in mineral oil). The mixture was refluxed with continuous removal of the distillate with replacement with fresh toluene when necessary for 1 hour. The cooled mixture was extracted with 1N HCl acid, the aqueous layer washed with water, dried over MgSO 4 and evaporated. The yield was 2.85 g (76%) of the title product as a mixture of diastereomers, structure confirmed by1 H-NMR. 1 H-NMR (DMSO-d 6): δ 0.80-0.95 (m, 3H), 1.20-1.40 (m, 6H), 1.40-1.90 (m, 4H), 1, 95-2.25 (m, 3H), 2.50-2.95 (m, 5H), 3.10-3.30 (m, 1H), 4.4 (bs, 1H, OH),  € ƒâ € ƒâ € ƒ4.82-4.94 (m, 41Ã-AND13539191 ·), 6.94-7.02 (m, 1H), 7.06-7.14 (m, 1H), 7.20-7.26 (m , 1H). MS: [M + 1] +: 338. (Compound also prepared following method c) Intermediate 1-2

Preparation of 2,3-diphenylpropionic acid (3R) -1-azabicyclo [2.2.2] oct-3-

Prepared using the same method as for intermediate 1-1, but starting with 2,3-diphenylpropionic acid methyl ester. The yield was 1.71 g (61.5%) of the title compound as a mixture of diastereomers. 1 H-NMR (DMSO-d 6): δ 1.05-1.20 (m, 1H), 1.30-1.60 (m, 3H), 1.65-1.75 (m, 1H), 2. (M, 4H), 2.85-3.10 (m, 2H), 3.20-3.40 (m, 1H) , 3.95-4.10 (m, 1H), 4.50-4.65 (m, 1H), 7.10-7.45 (m, 10H). MS: [M + 1] +: 336. (2,3-diphenylpropionic acid methyl ester can be prepared from commercially available 2,3-diphenylpropionic acid) 42 ΡΕ1353919

Intermediate 1-3

Preparation of 2-hydroxy-2-thien-2-ylpent-4-enoic acid (3R) -1-azabicyclo [2.2.2] oct-3-

Prepared using the same method as for Intermediate 1-1, but starting from 2-hydroxy-2-thien-2-ylpent-4-enoic acid methyl ester (Intermediate 1-10). The yield was 1.76 g (63.1%) of the title product as a mixture of diastereomers. 1 H-NMR (DMSOd 6): δ 1.25-1.80 (m, 4H), 1.80-2.10 (m, 1H), 2.50-3.05 (m, 7H), 3. , 10-3.35 (m, 2H), 4.55 (bs, 1H, OH), 4.75-4.95 (m, 1H), 5.10-5.30 (m, 2H), 5 (M, 1H), 7.10-7.20 (m, 1H), 7.20-7.30 (m, 1H) . MS: [M + 1] +: 308. (Compound also prepared following method c)

Intermediate 1-4

Preparation of 2-Cyclohexyl-2-fur-2-yl-2-hydroxyacetic acid (3R) -1-azabicyclo [2.2.2] oct-3-

Prepared using the same method as for Intermediate 1-1, but starting from 13.73 g (0.057 mol) of 2-cyclohexyl-2-fur-2-yl-2-hydroxy-4β, 13β, 13β (Intermediate 1-11) dissolved in 350 ml of toluene, 8.6 g (0.067 mol) of (3R) -3-hydroxy-1-azabicyclo [2.2.2] octane and 1.37 g 0342 mol) of HNa (60% dispersion in mineral oil). The oil obtained (10.33 g) was purified by silica gel chromatography eluting with 97: 3: 0.3 chloroform / methanol / ammonia. The appropriate fractions were combined and evaporated to give the two diastereomers: I-4a and I-4b.

Intermediate I-4a

Preparation of (2S) -2-cyclohexyl-2-fur-2-yl-2-hydroxy-acetic acid (3R) -1-azabicyclo [2.2.2] oct- an oil corresponding to the eluted diastereomer was first triturated with a 1: 1 mixture of ethyl ether / isopropyl ether to give 0.82 g (8.6%, based on the single isomer) of a solid whose structure was confirmed by 1H NMR as a pure diastereomer.

[Î ±] 22d = + 21.1 ° (c = 1, CHCl3)) 1 H-NMR (CDCl3): δ 1.10-1.45 (m, 8H), 1.45-1.60 (m, 2H), 1.60-1.85 (m, 4H), 1.94-2.02 (m, 1H), 2.26-2.38 (m, 2H), 2.70-2.92 (m, (m, 5H), 3.20-3.28 (m, 1H), 3.78 (bs, 1H, OH), 4.90 (m, 1H), 6.30-6.40 (m, 2H) , 7.40 (m, 1H). Î ± β13393919 MS: [M + 1] +: 334. The intermediate I-4a was hydrolyzed (EtOH / 2N NaOH, 2h at room temperature, 1h at 60 ° C), to give (+) - 2-cyclohexyl-2-fur-2-yl-2-hydroxyacetic acid: [Î ±] 22d = + 40.9 ° (c = 1, EtOH) The S-configuration was assigned (see TABLE 1)

Intermediate I-4b

Preparation of (2R) -2-cyclohexyl-2-fur-2-yl-2-hydroxy-acetic acid (3R) -1-azabicyclo [2.2.2] oct- an oil corresponding to the second eluted diastereomer was triturated with a 1: 1 mixture of ethyl ether / isopropyl ether to give 0.57 g (6%, based on a single isomer) of a solid whose structure was confirmed by1 H-NMR as a pure diastereomer. [α] D = -23.5 ° (c = 1, CHCl3)). 1 H-NMR (CDCl 3): δ1.10-1.50 (m, 8H), 1.50-1.90 (m, 6H), CM10C12 (m, 1H), 2.24-2 (M, 1H), 2.68-2.94 (m, 4H), 3.12-3.32 (m, 1H) 77 (bs, 1H, OH), 4.90 (m, 1H), 6.40 (m, 2H), 7.42 (m, 1H) 45 Ρ AND1353919 MS: [M + 1] +: 334.

Intermediate I-4b was hydrolyzed (EtOH / 2N NaOH, 2h at room temperature, 1h at 60øC) to give (-) - 2-cyclohexyl-2-fur-2-yl-2-hydroxyacetic acid : [Î ±] 22D = -39.7Â ° (c = 1, EtOH). The R configuration was assigned (see TABLE 1)

Intermediate 1-5

Preparation of 2-Cyclopentyl-2-hydroxy-2-phenylacetic acid (3R) -1-azabicyclo [2.2.2] oct-3-

Prepared using the same method as for intermediate 1-1, but starting with 13.5 g (0.0576 mol) 2-cyclopentyl-2-hydroxy-2-phenylacetic acid methyl ester (commercially available) dissolved (3R) -3-hydroxy-1-azabicyclo [2.2.2] octane and 0.91 g (0.023 mol) of HNa (60% dispersion in mineral oil). The yield was 13.1 g (69%) of the title product as a diastereomeric mixture oil, confirmed as 1 H-NMR. The two diastereomers I-5a and I-5b were separated after several crystallizations. 46 ΡΕ1353919

Intermediate I-5a

Preparation of (2R) -2-cyclopentyl-2-hydroxy-2-phenylacetic acid (3R) -1-azabicyclo [2.2.2] oct-3-yl ester Various treatments of the mixture of diastereomers in oil with different mixtures of diethyl ether / hexane and diisopropyl ether / hexane (cooling to -60 ° C) yielded 4.3 g of a white solid identified by 1 H-NMR as an enriched I-5a diastereomer. This solid was recrystallized twice from diethyl ether / hexane (cooling to 0 ° C) to give 2 g (21%) pure diastereomer.

[Î ±] 22d = -10.8Â ° (c = 1, CHCl3)). 1 H-NMR (CDCl 3): δ 1.25-1.80 (m, 11H), 1.80-1.95 (m, 1H), 2.05-2.15 (m, 1H), 2.40 2.50 (m, 1H), 2.62-3.05 (m, 5H), 3.05-3.18 (m, 1H), 3.80 (s, 1H, OH), 4.85-4.00 , 90 (m 1H), 7.22-7.42 (m, 3H), 7.60-7.75 (m, 2H). Intermediate I-5a was hydrolyzed (EtOH / 2N NaOH, 2h at room temperature and 2h at 60 ° C) to give (-) - 2-cyclopentyl-2-hydroxy-2-phenylacetic acid as an enantiomer neat: [Î ±] 22d = -1.52Â ° (c = 3, MeOH).

This value was specified as being of the R-configuration although in the literature (M. Mitsuya et al., Bioorg. Med. 47 ΡΕ1353919

Chem., (1999), 7, 2555-2567) the R-enantiomer was described with [a] 22D = -1.9 ° (c = 3, MeOH). (See TABLE 1)

Intermediate I-5b

Preparation of (2S) -2-cyclopentyl-2-hydroxy-2-phenyl-acetic acid (3R) -1-azabicyclo [2.2.2] oct-

The mother liquor from the first solid I-5a was evaporated and treated with maleic acid in isopropanol / diethyl ether. After cooling to 0-5 ° C, 7.0 g of a white solid were obtained and identified by1 H-NMR as the maleate salt of a mixture enriched with the second diastereomer I-5b. After three crystallizations of this product from acetonitrile / diethyl ether (1: 2.2), 2.4 g (18.7% based on the free base) of the maleate salt enriched with the second diastereomer I-5b (in 88:12 ratio, as determined by H-MN).

This maleate salt enriched with the second diastereomer I-5b (88:12) was treated with CHCl 3 and a solution of K 2 CO 3 to give the free base. I-5b (free base): = + 19.5 ° (c = 1, CHCl3) 48 ΡΕ1353919 1 H-NMR (CDCl3): δ 1.20-1.80 (m, 12H), 1.85-2, (M, 6H), 3.20-3.35 (m, 1H), 3.80 (s, 1H OH), 4.75-4.82 (m, m, 1H), 7.20-7.45 (m, 3H), 7.55-7.75 (m, 2). The signals corresponding to diastereomer I-5a (12%) were observed at 2.05-2.15, 2.40-2.50, 3.05-3.18, 4.85-4.90 ppm. The S configuration was assigned in view of the results obtained for the intermediate I-5a. (See TABLE D ·

Intermediate 1-6

Preparation of 2-Cyclohexyl-2-hydroxy-2-thien-2-ylacetic acid (3R) -1-azabicyclo [2.2.2] oct-3-

Prepared using the same method as for Intermediate 1-1, but from 16.2 g (0.064 mol) of 2-cyclohexyl-2-hydroxy-2-thien-2-ylacetic acid methyl ester ( Intermediate 1-12) dissolved in 400 ml of toluene, 9.5 g (0.074 mol) of (3R) -3-hydroxy-1-azabicyclo [2.2.2] octane and 1.51 g (0.038 mol) of HNa (60% dispersion in mineral oil). The oil obtained (10.97 g) was purified by silica gel chromatography, eluting with 95: 5: 0.5 chloroform / methanol / ammonia to give a pure product as a mixture of diastereomers, having the structure confirmed by1 H-NMR. Three crystallizations of this mixture in ethyl ether gave 1.68 g (15.2%) of a pure diastereomer (intermediate I-6a). The parent waters of the crystallizations were enriched with the other diastereomer (intermediate I-6b).

Intermediate I-6a

Preparation of (2S) -2-Cyclohexyl-2-hydroxy-2-thien-2-ylacetic acid (3R) -1-azabicyclo [2.2.2] oct-3-

[Î ±] 22d = -16.5Â ° (c = 1, CHCl3) 1 H-NMR (CDCl3): δ 1.05-1.85 (m, 13H), 1.85-2.0 (m, 1H) , 2.0-2.16 (m, 2H), 2.58-2.68 (m, 1H), 2.70-3.0 (m, 4H), 3.14-3.24 (m, 1H), 4.0 (s, 1H, OH), 4.90-5.0 (m, 1H), 6.95-7.05 (m, 1H), 7.10-7.15 (m, 1H), 7.20-7.30 (m, 1H). Intermediate I-6a was hydrolyzed (EtOH / 2N NaOH, 2h at room temperature, 1h at 60 ° C) to give (2S) -2-cyclohexyl- 2-hydroxy-2-thien-2-ylacetic acid: [Î ±] 22d = -15.1Â ° (c = 1, EtOH). The S setting has been assigned. (See TABLE 1). 50 ΡΕ1353919

Intermediate I-6b

Preparation of (2R) -2-Cyclohexyl-2-hydroxy-2-thien-2-yl-acetic acid (3R) -1-azabicyclo [2.2.2] oct-3- 1 H-NMR (CDCl 3): δ 1.05-2.0 (m, 14H), 2.0-2.20 (m, 2H), 2.65-3.02 (m, 5H), 3.24 (M, 1H), 4.0 (s, 1H, OH), 4.80-4.90 (m, 1H), 6.95-7.05 (m, 1H), 7.10- 7.20 (m, 1H), 7.20-7.30 (m, 1H). MS: [M + 1] +: 350. The R configuration was assigned in view of the results obtained with the intermediate I-6a. (See TABLE 1)

Intermediate 1-7

Preparation of (2S) -2-cyclopentyl-2-hydroxy-2-thien-2-ylacetic acid (3S) -1-azabicyclo [2.2.2] oct-3- 510 mg (0.00225 mol) of (2S) -2-cyclopentyl-2-hydroxy-2-thien-2-ylacetic acid (obtained by hydrolysis of intermediate I-15a) was dissolved in 7 ml of DMF. This solution was stirred at room temperature and 638 mg (0.00303 mol) of 1,1'-carbonyldiimidazole was added in several portions. After 4.5 hours the reaction mixture was cooled to 0 ° C and 315 mg (0.00248 mol) of (3S) -5β-and 13β-3919 3-hydroxy-1-azabicyclo [2.2.2] octane and 83 mg (0.0021 mol) of HNa (60% dipersion in mineral oil). After stirring at 112 h at room temperature the reaction mixture was treated with water and extracted three times with diethyl ether. The organic layers were combined, washed with brine and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was purified by silica gel column chromatography (eluent CHCl 3 / MeOH 15: 1) to afford 360 mg (47.6%) of the title product as an oil, having the structure confirmed by1 H-NMR.

[Î ±] 22d = -18.6Â ° (c = 1, CHCl3) 1 H-NMR (CDCl3): δ (same description as intermediate I-15b) MS: [M + 1] +: 336.

Intermediate 1-8

Preparation of (2R) -2-cyclohexyl-2-hydroxy-2-phenylacetic acid 1-azabicyclo [2.2.2] oct-4-yl ester.

Prepared using the same method as for intermediate 1-7, but starting with a solution of 600 mg (0.00282 mol) of (2R) -2-cyclohexyl-2-hydroxy-2-phenylacetic acid (obtained by hydrolysis of intermediate I-16a) in 9 ml of DMF was added 548 mg (0.00338 mol) of 1,1'-carbonyldiimidazole, 394 mg (0.0031 mol) of 4-hydroxy-1-azabicyclo [2.2.1] [2.2.2] octane and 104 mg (0.00259 mol) HNa (60% dispersion in mineral oil). After 44 h stirring at room temperature the reaction mixture was treated with water and extracted three times with diethyl ether. The organic layers were combined, washed with brine and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was purified by silica gel column chromatography with CHCl 3 to 15: 1 CHCl 3 / MeOH. The yield was 300 mg (31%) of the title product.

[Î ±] 22d = -27.6Â ° (c = 1, CHCl3) .1 H-NMR (CDCl3): Î'1.0-1.55 (m, 7H), 1.55-1.75 (m, 2H) , 1.75-1.85 (m, 1H), 1.85-2.05 (m, 6H), 2.10-2.22 (m, 1H), 2.90-3.10 (m, 6H), 3.60-3.80 (bs, 1H, OH), 7.20-7.40 (m, 3H), 7.57-7.67 (m, 2H). MS: [M + 1] +: 344.

Intermediate 1-9

Preparation of 2-hydroxy-2-thien-2-yl-heptanoic acid methyl ester. 50 ml of an ether solution of 0.0338 mol of pentylmagnesium bromide prepared from 5.1 g of 1-bromopentane (0.0338 mol) and 0.0372 mol of magnesium were added to a solution of 5 g of 2-oxo-2-thien-2-ylacetic acid methyl ester dissolved in 40 ml of a 53:39 ether / THF solution (50:50) at -70 ° C under N2 atmosphere. The mixture was stirred at this temperature for 10 minutes, and then warmed to room temperature. After 16 h, the reaction mixture was treated with saturated ammonium chloride solution and extracted three times with ethyl acetate. The organic phases were combined, washed with water, and dried with MgSO4. After removal of the solvent, the oil obtained was purified by column chromatography (silica gel) using hexane / EtOAc mixtures (25: 1 to 15: 1) as the eluent. The yield was 2.7 g (38%) of pure product, the structure of which was confirmed by1 H-NMR. 1 H-NMR (CDCl 3): δ 0.80-1.0 (m, 3H), 1.10-1.45 (m, 6H), 1.90-2.30 (m, 2H), 3.80 (s, 3H), 4.05 (s, 1H, OH), 7.0 (m, 1H), 7.10 (m, 1H), 7.30 (m, 1H). (2-oxo-2-thien-2-ylacetic acid methyl ester was prepared from commercially available 2-oxo-2-thien-2-ylacetic acid by a standard method).

Intermediate 1-10

Preparation of 2-hydroxy-2-thien-2-ylpent-4-enoic acid methyl ester.

Prepared from the same method as for intermediate 1-9. The yield was 1.92 g, 45.3%. NMR (CDCl3): δ 2.75-3.0 (m, 2H), 3.80 (s, 3H), 4.0 (s, 1H, OH), 5.10-5.30 m, 2H), 5.70-5.90 (m, 1H), 6.95-7.05 (m, 1H), 7.10-7.20 (m, 1H), 7.25-7.35 (m, 1H) MS: [Μ] = 212

Intermediate 1-11

Preparation of 2-Cyclohexyl-2-fur-2-yl-2-hydroxyacetic acid methyl ester.

Prepared using the same method as for intermediate 1-9, but starting from 73 ml (0.146 mol) of a solution of 2M cyclohexylmagnesium chloride in diethyl ether and 22.51 g (0.146 mol) of 2-fur-2-yl-2-oxoacetic acid (dissolved in 330 ml THF). The oil obtained was purified by column chromatography (silica gel) using a 9: 1 hexane / AcOEt mixture as the eluent. After removal of the solvent 13.73 g (39%) of a pure product was obtained, the structure of which was confirmed by MS and 1 H-NMR. 6H), 1.75-1.95 (m, 3.95 (s, 1H, OH), 1 H-NMR (CDCl3): δ 1.05-1.75 (m, 4H), 2.20- (M, 2H), 7.35-7.45 (m, 1H), MS: [M] + = 238 (2-fur-2-yl-2-oxoacetic acid methyl ester was prepared from commercially available 2-fur-2-yl-2-oxoacetic acid by a standard method).

Intermediate 1-12

Preparation of 2-Cyclohexyl-2-hydroxy-2-thien-2-ylacetic acid methyl ester. 98.6 ml (0.197 mol) of a 2M solution of cyclohexylmagnesium chloride in diethyl ether was added to a solution of 27.97 g (0.164 mol) of 2-oxo-2-thien-2 -acetic acid, dissolved in 370 mL of THF at -78 ° C under a N 2 atmosphere. The mixture was stirred at this temperature for 10 minutes, and then warmed to room temperature. After 1 h, the reaction mixture was treated with saturated ammonium chloride solution and extracted three times with ethyl acetate. The organic phases were combined, washed with water and dried with MgSO4. After removal of the solvent, the oil obtained was purified by column chromatography (silica gel) using hexane / AcOEt 90:10 as the eluent. The yield was 16.2 g (39.5%) of a pure product, the structure of which was confirmed by1 H-NMR. 1 H-NMR (CDCl3): δ 1.0-1.55 (m, 6H), 1.55-1.90 (m, 4H), 2.0-2.20 (m, 1H), 3.80 (s, 3H), 4.0 (s, 1H, OH), 7.0 (m, 1H), 7.10 (m, 1H), 7.20-7.30 (m, 1H). 56 ΡΕ1353919 MS: [M +]: 254. (The intermediate 1-12 is described in E. Atkinson et al., J. Med. Chem., (1977), Vol. 20, No. 12, 1612-1617)

Intermediate 1-13

Preparation of 2-cyclopentyl-2-hydroxy-2-thien-2-ylacetic acid methyl ester.

Prepared as in Example 1-12. The yield was 3.83 g (37%). 1 H-NMR (CDCl 3): δ 1.35-1.75 (m, 8H), 2.70-2.90 (m, 1H), 3.80 (s, 3H), 4.02 (s, 1H , OH), 6.95-7.05 (m, 1H), 7.10-7.20 (m, 1H), 7.20-7.25 (m, 1H). (Intermediate 1-13 is described in E. Atkinson et al., J. Med. Chem. (1977), Vol. 20, No. 12, 1612-1617)

Intermediate 1-14

Preparation of 2-Cyclopentyl-2-fur-2-yl-2-hydroxyacetic acid (3R) -1-azabicyclo [2.2.2] oct-3-

Cyclopentylmagnesium chloride, 0.0472 mol (23.6 ml of a 2M solution in ether) was added to a solution of ΡΕ1353919 9.4 g (0.0377 mol) of (3R) -1-azabicyclo [2.2.1] 2-yl] -2-oxoacetic acid, dissolved in 125 ml THF, at -70 ° C under N2 atmosphere. The mixture was stirred at this temperature for 10 minutes and then warmed to room temperature. After 16 h, the reaction mixture was treated with saturated ammonium chloride solution and extracted twice with ethyl acetate. The organic phases were combined, washed with water, and dried with MgSO4. After removal of the solvent, the obtained oil (7.5 g) was purified by silica gel chromatography eluting with 95: 5: 0.5 chloroform / methanol / ammonia. The appropriate fractions were combined and evaporated to give two diastereomers: I-14a, I-14b.

Intermediate I-14a

Preparation of (2S) -2-cyclopentyl-2-fur-2-yl-2-hydroxy-acetic acid (3R) -1-azabicyclo [2.2.2] oct-3- 1.55 g of an oil corresponding to the first eluted diastereomer was triturated with a 1: 1 mixture of isopropyl ether / petroleum ether to give 0.24 g (4%, based on a single isomer) of a solid whose structure was confirmed by1 H-NMR as pure diastereomer; m.p. = 109.6-110.6 ° C.

(CDCl3): δ 1.22-1.37 (m, 1H), 1.40-1.80 (m, 1H) 11H), 1.97 (m, 1H), 2.74-2.96 (m, 6H), 3.19-3.30 (m, 1H), 3.80 (bs, 1H, , 85-4.89 (m, 1H), 6.34-6.37 (m, 2H), 7.35 (m, 1H) MS: [M + 1] + = 320 Intermediate I-14a was hydrolyzed (EtOH / 2N NaOH, 2h at room temperature) to give (+) - 2-cyclopentyl-2-fur-2-yl-2-hydroxyacetic acid: [Î ±] 22d = + 31.95Â ° (c = 1 , EtOH) The S configuration was assigned. (See TABLE 1). Intermediate I-14b

Preparation of (2R) -2-cyclopentyl-2-fur-2-yl-2-hydroxy-acetic acid (3R) -1-azabicyclo [2.2.2] oct-3- 1.10 g of a solid corresponding to the second eluted diastereomer was triturated with a 1: 1 mixture of isopropyl ether / petroleum ether to give 0.42 g (7%, based on a single isomer) of a solid whose structure was confirmed by1 H-NMR as a pure diastereomer; mp = 119.9-122.1 ° C. = -14.2 ° (c = 1, CHCl3) [Î ±] 22

(M, 12H), 2.07 (m, 1H), 2.48-2.56 (m, 1H), 2.67 (m, 1H), 2.67 (M, 5H), 3.12-3.24 (m, 1H), 3.80 (bs, 1H, OH), 4.87-4.91 (m, 1H), 6.35- MS: [M + 1] + = 320 Intermediate I-14b was hydrolyzed (EtOH / 2N NaOH, 2h at room temperature) to give ( 2-fur-2-yl-2-hydroxyacetic acid: [Î ±] 22d = -32.10Â ° (c = 1, EtOH) The R configuration was assigned. (See TABLE 1). (2-fur-2-yl-2-oxoacetic acid (3R) -1-azabicyclo [2.2.2] oct-3-yl ester can be prepared as described in WO 01/04118.

Intermediate 1-15

Preparation of 2-Cyclopentyl-2-hydroxy-2-thien-2-ylacetic acid (3R) -1-azabicyclo [2.2.2] oct-3-

Prepared using the same method as for intermediate 1-14, but from 20.8 g (0.0784 mol) of the acid method (3R) -1-azabicyclo [2.2.2] oct-3- ΡΕ1353919 2-oxo-2-thien-2-ylacetic acid and cyclopentylmagnesium chloride, 0.08 mol (40 ml of a 2M solution in ether). The oil obtained (15.64 g) was purified by silica gel chromatography eluting with 97: 3: 0.5 chloroform / methanol / ammonia to give 8.38 g (32%) of pure product, diastereomeric mixture: I-15a and I-15b. The structure was confirmed by1 H-NMR.

Intermediate I-15a

Preparation of (2S) -2-cyclopentyl-2-hydroxy-2-thien-2-ylacetic acid (3R) -1-azabicyclo [2.2.2] oct-3- The mixture of diastereomers in oil was treated with isopropyl ether to give a solid which was further treated with isopropyl ether to give 2.2 g of a pure diastereomer (I-15a intermediate, 16.7% based on a single isomer) .

[Î ±] 22d = -5.75Â ° (c = 1, CHCl3); mp: 152-157 ° C 1 H-NMR (CDCl 3): δ 1.40-1.80 (m, 11H), 1.80-2.0 (m, 1H), 2.10 (m, 1H), 2.52-2.65 (m, 1H), 2.70-2.95 (m, 5H) 3.10-3.22 (m, 1H), 4.07 (s, 1H, OH), 4. , 85-4.95 (m, 1H), 6.95-7.05 (m, 1H), 7.10-7.20 (m, 1H), 7.20-7.27 (m, 1H). Intermediate I-15a was hydrolyzed (EtOH / 2N NaOH, 2h at room temperature, and 2h at 60 ° C) to give (-) - 2-cyclopentyl-2-hydroxy acid -2-thien-2-ylacetic acid: [Î ±] 22D = -64.4Â ° (c = 1, EtOH). The S setting has been assigned. (See TABLE 1).

Intermediate I-15b

Preparation of (2R) -2-cyclopentyl-2-hydroxy-2-thien-2-ylacetic acid (3R) -1-azabicyclo [2.2.2] oct-3-

The mother liquor from the first crystallization of intermediate I-15a was evaporated and the oil obtained was treated with isopropyl ether to give a solid, which was treated again with isopropyl ether to give 1.47 g of the second diastereomer, intermediate I-15b ( 11.2%, based on a single isomer).

[Î ±] ISO: O (II): K): 49 (c = 1, CHCl3); mp: 99-102Â ° C. 2 H-NMR (CDCl3: 1: δ 1.25-1.85 (m, 12H), 2.0 (m, 1H), 2.65-2.95 , 6H), 3.22-3.34 (m, 1H), 4.05 (s, 1H, OH), 4.80-4.92 (m, 1H), 6.90-7.0 (m, 1H), 7.10-7.16 (m, 1H), 7.20-7.77 (m, 1H) MS: [M + 1] + = 336 62 ΡΕ1353919 Intermediate I-15b was hydrolyzed (EtOH / 2N NaOH, 2h at room temperature and 2h at 60øC) to give (+) - 2-cyclopentyl-2-hydroxy-2-thien-2-ylacetic acid: [Î ±] 22d = +6.63 Intermediate I-15a and I-15b were also prepared following method c) (0R) -1-azabicyclo [2.2.1] heptane- 2.2.2] oct-3-yl ester can be prepared as described in WO 01/04118)

Intermediate 1-16

Preparation of 2-Cyclohexyl-2-hydroxy-2-phenylacetic acid (3R) -1-azabicyclo [2.2.2] oct-3-yl ester.

Cyclohexylmagnesium chloride, 0.127 mol (63.6 ml of a 2M solution in ether) was added to a solution of 28.7 g (0.111 mol) of (3R) -1-azabicyclo [2.2.2] octane ester -3-yl ester dissolved in 350 ml of THF at -70 ° C under N 2 atmosphere. The mixture was stirred at this temperature for 10 minutes, and then warmed to room temperature. After 1h, the reaction mixture was treated with saturated ammonium chloride solution and extracted twice with ethyl acetate. The organic phases were combined, washed with water and dried with 63 ΡΕ1353919

MgSO 4. After removal of the solvent, the oil obtained (27.0 g) was purified by silica gel chromatography eluting with 10: 1 chloroform / methanol. The yield was 18.7 g (49.2%) of pure product, mixture of diastereomers: I-16a and I-16b.

Intermediate I-16a

Preparation of (2R) -2-cyclohexyl-2-hydroxy-2-phenylacetic acid (3R) -1-azabicyclo [2.2.2] oct-3- 16 g of the oil of the diastereomeric mixture was dissolved in isopropanol and treated with 5.4 g of fumaric acid. After cooling to 0-5øC, 8 g of the fumarate salt of the first diastereomer (intermediate I-16a) was obtained.

Fumarate salt: MS: [M (free base) + 1] + = 344. 8 g of this salt were recrystallized from isopropanol to obtain 5 g of a more pure product. This salt was treated with CHCl 3 and a K 2 CO 3 solution to give the free base intermediate I-16a. I-16a (free base): [Î ±] 22d = -14.9Â ° (c = 1, CHCl3). 64 ΡΕ1353919 1 H-NMR (CDCl3): δ 1.0-1.95 (m, 14H), 2.04-2.12 (m, 1H), 2.16-2.32 (m, 1H), 2 (M, 4H), 3.04-3.16 (m, 1H), 3.70-3.85 (s, 1H, OH), 4.85-4.90 (m, 1H), 7.25-7.40 (m, 3H), 7.60-7.70 (m, 2H). Intermediate I-16a (free base) was hydrolyzed (EtOH / 2N NaOH, 7h at 60 ° C) to give (-) - 2-cyclohexyl-2-hydroxy-2-phenylacetic acid as pure enantiomer [ Î ±] 22d = -23.6Â ° (c = 1.4, EtOH). This value was assigned to the R configuration although in the literature (A. Tambuté, A. Collet, Bulletin de la Societe Chimique de France, 1984, No. 1-2, pages 11-77 to 11-82) Cyclohexyl-2-hydroxy-2-phenylacetic acid was described as [α] 24 D = + 25.2 ° (c = 1.4, EtOH). (See TABLE 1).

Intermediate I-16b

Preparation of (2S) -2-cyclohexyl-2-hydroxy-2-phenylacetic acid (3R) -1-azabicyclo [2.2.2] oct-3-

The mother liquor from the fumarate salt of intermediate I-16 was evaporated and the residue was dissolved in water. The obtained solution was washed with ether, made basic with K 2 CO 3 and extracted with CHCl 3. The organic layer was dried with MgSO4 and the solvent was evaporated. The oil obtained (7.5 g) was dissolved in 50 ml of isopropanol and treated with EtOH / HCl (g). After addition of 75 ml of ethyl ether, 3.1 g of the hydrochloride salt of the second diastereomer, intermediate I-16b, was obtained.

Hydrochloride salt: MS: [M (free base) + 1] + = 344. The hydrochloride salt was treated with CHCl 3 and a K 2 CO 3 solution to obtain intermediate I-16b free base. 1-16 b (free base): [Î ±] 22d = + 25.3Â ° (c = 1, CHCl3). 1 H-NMR (CDCl3): δ 1.0-1.78 (m, 13H); 1.78-1.90 (m, 1H), 1.92-2.0 (m, 1H), 2.20-2.34 (m, 1H), 2.66-2.96 (m, 5H ), 3.20-3.32 (m, 1H), 3.70-3.85 (s, 1H, OH), 4.75-4.85 (m, 1H), 7.25-7.40 m, 3H), 7.60-7.70 (m, 2H). Intermediate I-16b (free base) was hydrolysed (EtOH / 2N NaOH, 60øC, 8h) to give (+) - 2-cyclohexyl-2-hydroxy-2-phenylacetic acid as a enan-thiomer [Î ±] 22d = + 23.1Â ° (c = 1.4, EtOH). This value was assigned to the S configuration according to the results obtained with the intermediate I-16a. (See TABLE 1). (2-Oxo-2-phenylacetic acid (3R) -1-azabicyclo [2.2.2] oct-3-yl ester can be prepared as described in WO 92/04346 = 66 ΡΕ1353919

Intermediate 1-17

Preparation of 2-Hydroxy-2,3-diphenylpropionic acid (3R) -1-azabicyclo [2.2.2] oct-3-yl ester.

Prepared using the same method as for intermediate 1-16 as a mixture of diastereomers 1-11a and I-17b, which was separated by crystallization using ether / isopropyl ether.

Intermediate I-17a

Preparation of (2R) -2-Hydroxy-2,3-diphenylpropionic acid (3R) -1-azabicyclo [2.2.2] oct-3-yl ester. The yield was 0.87 g (42.6% based on a single isomer), mp: 132 ° C. 1 H-NMR (CDCl 3): δ 1.30-1.60 (m, 2H), 1.60-1.90 (m, 2H), 2.05 (m, 1H), 2.20-2.35 (m, 1H), 2.50-2.90 (m, 4H), 3.0-3.15 (m, 1H), 3.25 and 3.60 (dd, 2H), 3.70 (bs , 1H), 4.70-4.80 (m, 1H), 7.15-7.45 (m, 8H), 7.65-7.75 (m, 2H). MS: [M + 1] + = 352 ((*): Configuration not assigned) 67 ΡΕ1353919

Intermediate I-17b

Preparation of (2R) -2-Hydroxy-2,3-diphenylpropionic acid (3R) -1-azabicyclo [2.2.2] oct-3-yl ester. The yield was 0.23 g (11.2% based on a single isomer), mp: 107 ° C. 1 H-NMR (CDCl 3): δ 1.20-1.35 (m, 1H), 1.35-1.55 (m 2H), 1.55-1.70 (m, 1H), 1.80- 1.95 (m, 1H), 2.55-2.90 (m, 5H), 3.10-3.20 (m, 1H), 3.25 and 3.60 (dd, 2H), 3.80 (bs, 1H OH), 4.65-4.80 (m, 1H), 7.20-7.50 (m, 8H), 7.65-7.75 (m 2H). MS: [M + 1] + = 352 ((*): Configuration not assigned)

Intermediate 1-18

Preparation of 2-Hydroxy-3-phenyl-2-thien-2-ylpropionic acid (3R) -1-azabicyclo [2.2.2] oct-3-

Prepared using the same method as for Intermediate 1-15 as a mixture of diastereomers. The yield was 0.81 g (54%). The product was purified by the preparation of the hydrochloride salt, 0.57 g of this salt (63% of the free base) was obtained. ΡΕ1353919 68

Hydrochloride salt: 1 H-NMR (CDCl 3): δ 1.40-1.60 (m, 1H), 1.60-1.95 (m, 3H), 2.05 and 2.10 (m, 1H), 2.75-3.65 (m, 8H), 4.90-5.05 (m, 1H), 6.50 and 6.55 (s, 1H, OH), 6.95-7.05 , 1H), 7.10-7.30 (m, 6H), 7.40-7.50 (m, 1H), 10.9 (bs, 1H, NH +) MS: [M + = 306

Intermediate 1-19

Preparation of 2-Hydroxy-2-thien-2-ylpent-3-ynoic acid (3R) -1-azabicyclo [2.2.2] oct-3-

Prepared using the same method as for Intermediate 1-15 as a mixture of diastereomers. The yield was 1.88 g (25.6%). 1 H-NMR (CDCl 3): δ 1.20-1.90 (m, 4H), 1.92 and 1.96 (s, 3H, CH3), 2.0 and 2.16 (m, 1H), 2. , 45-2.90 (m, 5H), 3.05-3.20 and 3.15-3.27 (m, 1H), 4.85-4.92 (m, 1H), 6.94- 7.0 (m, 1H), 7.24-7.30 (m, 2H), the OH group signal is observed between 4.5 and 5.5 as a broad band. MS: [M + 1] + = 306 69 ΡΕ1353919

Intermediate 1-20

Preparation of 2-Hydroxy-2-thien-2-ylbut-3-enoic acid (3R) -1-azabicyclo [2.2.2] oct-3-

Prepared using the same method as for Intermediate 1-15 as a mixture of diastereomers. The yield was 1.74 g (18.8%). 1 H-NMR (CDCl 3): δ 1.30-1.90 (m, 4H), 2.05-2.15 (m, 1H), 2.60-3.0 (m, 5H), 3.15 3.35 (m, 1H), 3.40-4.70 (broad band, 1H, OH), 4.85-4.95 (m, 1H), 5.30-5.40 (m, 1H ), 5.60-5.75 (m, 1H), 6.30-6.50 (m, 1H), 6.95-7.05 (1H), 7.10-7.15 (m, 1H ), 7.25-7.30 (m, 1H). MS: [M + 1] + = 294

Intermediate 1-21

Preparation of 2-Hydroxy-4-phenyl-2-thien-2-yl-butyric acid (3R) -1-azabicyclo [2.2.2] oct-3-

Prepared using the same method as for Intermediate 1-15 as a mixture of diastereomers. The yield was 0.29 g (2.4%). 1 H-NMR (CDCl 3): δ 1.25-1.95 (m, 4H), 1.95-2.10 (m, 70 ΡΕ1353919 1 Η), 2.30-3.0 (m, 9H), 3. (M, 1H), 6.95-7.05 (m, 1H), 7.05-7.40 (m, 7H) . MS: [M + 1] + = 372 Method -and-

Intermediate 1-22

Preparation of 2-hydroxymethyl-2,3-diphenylpropionic acid (3R) -1-azabicyclo [2.2.2] oct-3-yl ester. 2.40 ml of lithium diisopropylamide (0.0048 mol) in a 2M solution (in hepatane / THF / benzene) was added to a stirred solution of (3R) -1- azabicyclo [2.2.2] oct-3-yl ester in 30 ml of THF at -70 ° C under a T 2 atmosphere. CH2O (gaseous) was bubbled into the reaction mixture with a stable stream of dry N2 for 10 min at -70 ° C and then while the mixture was warmed to room temperature. The reaction was quenched by addition of saturated ammonium chloride solution (100 ml) and the resulting mixture was extracted twice with 100 ml of ethyl acetate. The organic layers were combined, dried over MgSO4 and evaporated to give 1.9 g of an oil. These 1.9 g were combined with 3.28 g of a previous preparation and the product obtained (5.18 g) was purified by chromatography on silica gel eluting with chloroform / methanol / ammonia, 97.5: 2.5: 0.25 to 90: 10: 1. Appropriate fractions 71 ΡΕ1353919 were combined and evaporated to give the two diastereomers: intermediates I-22a and I-22b.

Intermediate I-22a:

Preparation of (2R) -2-Hydroxymethyl-2,3-diphenylpropionic acid (3R) -1-azabicyclo [2.2.2] oct-3-yl ester. 1.25 g of the solid corresponding to the first eluted diastereomer was triturated with isopropyl ether to give 0.95 g (42%, based on a single isomer) of a white solid whose structure was confirmed by1 H-NMR as pure diastereomer: mp : 119Â ° C. 1 H-NMR (CDCl 3): δ 1.20-1.35 (m, 1H), 1.40-1.70 (m, 3H), 1.90 (m, 1H), 2.5 (bs, OH ), 2.60-2.85 (m, 5H), 3.15-3.25 (m, 1H), 3.40-3.50 (dd, 2H), 3.95-4.10 (dd, , 2H), 4.85 (m, 1H), 7.05 (m, 2H), 7.15-7.40 (m, 8H) MS: [M + 1] + = 366 ( not assigned)

Intermediate I-22b

Preparation of (2R) -2-Hydroxymethyl-2,3-diphenylpropionic acid (3R) -1-azabicyclo [2.2.2] oct-3-yl ester. 1.84 g of an oil corresponding to the second 72 Ρ E1353919 eluted diastereomer was purified by column chromatography (under the conditions described above) to give 1.26 g of a solid which, after trituration with isopropyl ether, yielded 0.95 g of a white solid whose structure was combined by 1 H-NMR as pure diastereomer (42%, based on a single isomer); mp: 154 ° C. 1 H-NMR (CDCl 3): δ 1.20-1.35 (m, 1H), 1.50-1.75 (m, 3H), 2.0 (m, 1H), 2.35 (bs , OH), 2.45-3.80 (m, 5H), 3.10-3.20 (m, 1H), 3.35-3.50 (dd, 2H), 3.95 MS: [M + 1] + = 366 (m, 2H), 7.10 (dd, 2H), 4.85 (m, 1H), 7.0 (m, 2H), 7.15-7.40 (m, 8H) (*): Configuration not assigned)

Also included within the scope of the present invention are pharmaceutical compositions comprising, as active ingredient, at least one quinuclidine derivative of formula (I) in association with a pharmaceutically acceptable carrier or diluent. Preferably the composition is made in a form suitable for oral administration.

Pharmaceutically acceptable carriers or diluents which are admixed with the active compound (s) to form the composition of this invention are well known per se and the excipients used herein are dependent upon, inter alia, the method of administration of the composition.

The compositions of this invention are preferably adapted for oral administration. In this case, the composition for oral administration may take the form of tablets, film-coated tablets, inhalation liquids, inhalation powders and inhalation aerosols; all containing one or more compounds of the invention; such preparations can be made by methods well known in the art.

Diluents which may be used in the preparation of the compositions include liquid and solid diluents which are compatible with the active ingredient together with color or flavoring agents if desired. The tablets or film-coated tablets may conveniently contain 1 to 500 mg, preferably 5 to 300 mg of active ingredient. The inhalation compositions may contain from 1æg to 1000æg, preferably from 10æg to 800æg active ingredient. In human therapy, the dose of the compound of formula (I) depends on the desired effect and the duration of the treatment; the dosages for adults are generally between 3 mg and 300 mg per day in the form of tablets and between 10 pg and 800 pg per day as the inhalation composition. 74 ΡΕ1353919

Pharmacological Action

Results regarding binding to human muscarinic receptors and the bronchospasm test in guinea pigs were obtained as described below.

Human muscarinic receptor studies [3H] -NMS binding to human muscarinic receptors was performed according to Waelbroek et al. (1990), Mol Pharmacol., 38: 275-273. The assays were performed at 25 ° C. Membrane preparations of stably transfected Chinese (KCH) ovarian Kl cells expressing the human muscarinic M3 receptor genes were used.

For determination of IC50, the membrane preparations were suspended in DPBS to the final concentration of 89 pg / ml for the M3 subtype. The membrane suspension was incubated with the tritiated compound for 60 minutes. After incubation the membrane fraction was filtered off and the binding radioactivity was determined. Non-specific binding was determined by the addition of 10-4 M atropine. At least six duplicate concentrations were evaluated to generate individual shift curves.

Our results show that the compounds of the present invention have high affinities for muscarinic M3 receptors, preferably human muscarinic 75 ΡΕ1353919 receptors. Affinity levels were measured by in vitro assays as described above at 100 nM and 10 nM. Preferred compounds of the invention produce an inhibition of [3H] -NMS binding of at least 35% at 10 nM and at least 65% at 100 nM (Table 2). TABLE 2 COMPOUND NUMBER% INHIBITION concentration: 1.00E-07 M% INHIBITION concentration: 1.00E-08 M Atropine 88.3 69.79 Ipratropium bromide 93.75 67.25 13 76 36 14 76.5 39, 0 16 74.2 36.3 23 81.5 72 23 75.6 63.3 24 78 56, 6 25 76, 1 62, 6 26 75, 6 63, 8 28 78.3 60, 6 29 79.0 53, 8 31 74.3 54.3 32 73, 9 44.5 33 72.8 46, 7 34 85, 3 68.3 36 84.2 42.0 37 88.1 72.6 76 ΡΕ1353919 (cont'd) N ° COMPOUND% INHIBITION% INHIBITION concentration: concentration: 1.00E-07 M 1.00E-08 M 38 86, 3 57.7 40 86, 9 72.7 43 83.4 58.7 44 84, 6 46 87.1 57.6 53 81.5 58 54 72.5 44.1 56 77.3 53.8 57 77.4 47.1 61 75, 1 39, 9 64 78, 6 64.5 65 79 , 8 66, 0 67 75, 1 52.5 69 70.8 43, 9 70 71.2 50.0 80 72.4 55, 8 81 70.1 45.4 82 70, 6 55.3 83 72, 7 60.3 84 68.3 41.0 86 68.2 37.2 88 65.5 35.7 89 68.5 51.3 92 69.4 49.2 77 ΡΕ1353919

Tests of bronchospasm in guinea pigs (guinea pigs)

The studies were conducted according to H. Konzett and F. Rössler (1940), Arch. Exp. Path. Pharmacol. 195: 71-74. Aqueous solutions of the agents to be tested were nebulized and inhaled by guinea pigs (Dunkin-Hartley). Bronchial response to stimulation with intravenous acetylcholine was determined before and after drug administration and changes in lung resistance at various time points were expressed as a percentage of inhibition of bronchospasm.

The compounds of the present invention inhibited the bronchospasm response to acetylcholine with high potency and a long duration of action. diverticulitis and From the above described results one skilled in the art can readily appreciate that the compounds of the present invention have excellent antimuscarinic activity (M3) and thus are useful for the treatment of diseases in which the muscarinic M3 receptor is including respiratory diseases such as chronic obstructive pulmonary disease (COPD), bronchitis, bronchial hyperreactivity, asthma, cough and rhinitis; urological diseases, such as urinary incontinence, polaciria, neurogenic or unstable bladder, cytospasm and chronic cystitis; gastrointestinal disorders, such as irritable bowel syndrome, spastic colitis, peptic ulceration; and cardiovascular diseases, such as vaginally induced sinusoidal bradycardia. For example, the compounds of the present invention are useful for the treatment of respiratory diseases, such as chronic obstructive pulmonary disease, chronic bronchitis, asthma and rhinitis; urological diseases, such as urinary incontinence and polaciuria in neuripenia polaciuria, neurogenic bladder, nocturnal enuresis, unstable bladder, cytospasm and chronic cystitis; and gastrointestinal diseases, such as irritable bowel syndrome, spastic colitis, colitis, and diverticitis. The present invention further provides a compound of formula (I) or a pharmaceutically acceptable composition comprising a compound of formula (I) for use in a method of treating the body of humans or animals through therapy, in particular for the treatment of an illness or a respiratory, urological or gastrointestinal problem. The present invention further provides the use of a compound of formula (I) or a pharmaceutically acceptable composition comprising a compound of formula (I) for the manufacture of a medicament for the treatment of a respiratory, urological or gastrointestinal disease or problem .

In addition, the compounds of formula (I) and the pharmaceutical compositions comprising a compound of formula (I) may be used to treat a respiratory, urological or gastrointestinal disease or problem, which method comprises administering to a patient (I) or of a pharmaceutical composition comprising a compound of formula (I). A compound of formula (I) or a pharmaceutical composition comprising a compound of formula (I).

In addition, the compounds of formula (I) and pharmaceutical compositions comprising a compound of formula (I) may be used in combination with other drugs effective in treating such diseases. For example, with β 2 agonists, steroids, antiallergic drugs, phosphodiesterase IV inhibitors and / or leukotriene D4 (LTD4) inhibitors, for simultaneous, separate or sequential use in the treatment of a respiratory disease. The present invention therefore provides a combination product comprising (i) a compound according to the invention; and (ii) another compound effective in the treatment of a respiratory, urological or gastrointestinal disease or problem for simultaneous, separate or sequential use. The compound (ii) which is effective in the treatment of a respiratory, urological or gastrointestinal disease or problem may be a β 2 agonist, steroid, antiallergic drug, phosphodiesterase IV inhibitor and / or leukotriene D4 (LTD4) antagonist when the compound product is for simultaneous, separate or sequential use in the treatment of a respiratory disease. The present invention will be further illustrated by the following examples. The examples are given for illustration only and are not construed as limiting.

Example 1

(3R) -3- (2,3-Diphenylpropionyloxy) -1- (3-phenoxypropyl) -1-azoniabicyclo [2.2.2] octane trifluoroacetate. The title compound was synthesized as a mixture of diastereomers according to methods c and b from intermediate 1-2. The yield of the final step was 20 mg, 71%. MS [M-CF 3 COO] +: 470 1 H-NMR (DMSO-d 6): δ 1.50-1.72 (m, 2H), 1.75-1.95 (m, 2H), 1.97-2 (M, 3H), 2.95-3.15 (m, 4H), 3.20-3.50 (m, 5H), 3.75-3.85 (m, 1H), 3.95 (M, 3H), 4.95-5.05 (m, 1H), 6.90-7.0 (m, 4H), 7.15-7.45 (m, 11H) ΡΕ1353919

Example 2

(3R) -3- (2,3-Diphenylpropynyloxy) -1- (3-thien-2-ylpropyl) -1-azoniabicyclo [2.2.2] octane trifluoroacetate. The title compound was synthesized as a mixture of diastereomers according to methods c and b from intermediate 1-2. The yield of the final step was 15 mg, 55%. MS [M-CF 3 COO] +: 460 1 H-NMR (DMSO-d 6): δ 1.50-1.70 (m, 2H), 1.70-2.0 (m, 4H), 2.0-2 (M, 1H), 2.75-2.85 (m, 2H), 2.85-3.20 (m, 4H), 3.20-3.45 (m, 5H), 3.70- 3.82 (m, 1H), 4.02-4.12 (m, 1H), 4.95-5.02 (m, 1H), 6.90-7.05 (m, 2H), 7.10 -7.45 (m, 11H).

Example 3

(3R) -3 - [(2R) -2-hydroxymethyl-2,3-diphenylpropionyloxy] -1- (3-thien-2-ylpropyl) -1-azonia-bicyclo [2.2.2] octane trifluoroacetate (diastereomer 1) The title compound was synthesized according to the methods and, starting from intermediate I-22a. The yield of the final step was 15 mg, 52%. ΔΕ1353919 82 MS [M-CF3 COO] +: 490 1 H-NMR (DMSO-d6): δ 1 LO 1.75 (m, 2H), 1.75-2.0! (m, 4H), 2.21 (m, 1H), 2.75-2.85 (m, 2H), 2.85-2.95 (m, 1H), 3.05-3.45 (m, 8H), 3.75-3.87 (m, 2H), 3.92-4.0 (m, 1H), 5.08 (m, 1H), 5.20-5.23 (t, 1H, OH ), 6.82-6.90 (m 2H), 6.90-6.95 (m, 1H), 6.95-7.02 (m, 1H), 7.05-7.20 (m, m 5H), 7:20- 7,35 (m, 3H), 7 ', 37-7.42 (m, 1H).

Example 4

(3R) -3 - [(2R) -2-hydroxymethyl-2,3-diphenylpropionyloxy] -1-phenethyl-1-azoniabicyclo [2.2.2] octane (diastereomer 1) trifluoroacetate The title compound was synthesized from according to the methods and, from intermediate I-22a. The yield of the final step was 18 mg, 64%. MS [M-CF 3 COO] +: 470 1 H-NMR (DMSOd 6): δ 1.62-1.75 (m, 2H), 1.80-2.05 (m, 2H), 2.26 m, 1H), 2.90-3.12 (m, 3H), 3.20-3.55 (m, co 3.80-4.02 (m, 3H), 5.10-5.17 (m, m, 1H), 5.22-5.25 (t, 1H, OH), 6.82-6.90 (m, 2H), 7.10-7.20 (m, 5H), 7.22- 7.40 (m, 8H) 83 ΡΕ1353919

Example 5

(3R) -3 - [(2R) -2-hydroxymethyl-2,3-diphenylpropionyloxy] -1- (3-thien-2-ylpropyl) -1-azonia-bicyclo [2.2.2] octane trifluoroacetate (diastereomer 2) The title compound was synthesized according to the methods and, starting from intermediate I-22b. The yield of the final step was 10.1 mg, 37.5%. MS [M-CF 3 COO] +: 490 1 H-NMR (DMSO-d 6): δ 1.45-1.60 (m, 1H), 1.60-3.75 (m, 1H) -2.05 (m, 4H), 2.18 (m, 1H), 2.75-2.30 (m, 2H), 2.95-3.10 (m, 1H) (M, 8H), 3.75-3.92 (m, 2H), 4.0-4.12 (m, 1H), 5.05-5.15 (m, 1H ), 5.25-5.35 (t, 1H, OH), 6.70-6.85 (m, 2H), 6.90-7.20 (m, 7H), 7.20-7 , 35 (m, 3H), 7.35-7.42 (m, 1H).

Example 6

(3R) -3 - [(2 *) -2-Hydroxymethyl-2,3-diphenylpropionyloxy] -1-phenethyl-1-azoniabicyclo [2.2.2] octane (diastereomer 2) trifluoroacetate The title compound was synthesized from according to the methods and, from intermediate I-22b. The yield of the final step was 22 mg, 76%. ΡΕ1353919 84 MS [M-CF3 COO] +: 470 1 H-NMR (DMSO-d6): δ1.50-1.60 (m, 1H), 1.60-6.81 (m, 1H) (M, 1H), 2.90-3.31 (m, 2H), 3.13-3.55 (m, 9H), 3.78 (M, 1H), 4.50 (m, 1H), 3.85 (m, 1H) , 5.35-5.40 (t 1H, OH), 6.75-6.80 (m, 2H), 7.0-7.15 (m, 3H), 7.120-7.40 (m, 8H).

Example 7

(3R) -3 - [(2R) -2-hydroxy-2,3-diphenylpropyryloxy] -1- (3-phenoxypropyl) -1-azoniabicyclo [2.2.2] octane bromide (diastereomer 1) The compound of the title was synthesized according to methods d, and from intermediate I-17a. The yield of the final step was 380 mg, 96%. MS [M-Br] + co 5, mp: 1.80 (m, 2H), 1.75-2.02 (m, , 2H), 2.02-2.15 (m, 2H), 2.24 (m, 1H), 3.05-3.25 (m, 2H), 3.25-3.55 (m, 7H), 3.78-3.90 (m, 1H), 3.98-4.88 (m, 2H), 5.02-5.10 (m, 1H), 6.20 (s, 1H , OH), 1.6 92-7.0 (m, 3H), 7.10-7.22 (m, 5H), 7.25-7.40 (m, 5H), 7.52-7, 58 (m, 2H) φ 85 ΡΕ1353919

Example 8

(3R) -3 - [(2R) -2-hydroxy-2,3-diphenylpropyryloxy] -1- (2-phenoxypropyl) -1-azoniabicyclo [2.2.2] octane bromide (diastereomer 1) The compound of the title was synthesized according to methods d, and from intermediate I-17a. The yield of the final step was 320 mg, 83%.

MS [M-Br] +: 472, mp: 223 ° C 1 H-NMR (DMSO-d 6): δ 1.70-1.80 (m, 2H), 1.80-2.0 (m, 2H), 2H), 3.15-3.55 (m, 7H), 3.55-3.50 (m 2H), 3.85-4.0 (m, 1H) (M, 2H), 5.0-5.10 (m, 1H), 6.10 (s, 1H, OH), 6.90-7.05 (m, 3H), 7.05 - 7.20 (m, 5H) 7.20 - 7.40 (m, 5H),, 7.45-7.55 (m, 2H).

Example 9

(3R) -3 - [(2R) -2-hydroxy-2,3-diphenylpropionyloxy] -1- (3-phenoxypropyl) -1-azoniabicyclo [2.2.2] octane trifluoroacetate (diastereomer 2) The title compound The title compound was synthesized according to methods d, and from intermediate I-17b. The yield of the final step was 7.2 mg, 25%. MS [M-CF 3 COO] +: 486 86 ΡΕ1353919 1 H-NMR Î'-MS-d6): δ1.10-5.55 (m, 1H), 1.55-1.7 (m, 1H), 1 (M, 3H), 3.00-3.60 (m, 9H), 3.77-3.87 (m, 1H), 4.75 (m, (M, 1H), 6.1 (s, 1H, OH), 6.90-7.00 (m, 3H), , 15.7, 25.25 (m, 5H), 7.25-7.42 (m, 5H), 7.60-7.67 (m, 2H),

Example 10

(3R) -3 - [(2R) -2-hydroxy-2,3-diphenylpropionyloxy] -1- (2-phenoxyethyl) -1-azoniabicyclo [2.2.2] octane trifluoroacetate (diastereomer 2) The The title compound was synthesized according to methods d, and from intermediate I-17b. The yield of the final step was 5.4 mg, 19%. MS [M-CF 3 COO] +: 472 1H-NMR (DMSO-d6): δ 1.40-1.55 (m, 1H), 1.55-1.70 (m, 1H), 1.80-2 (M, 2H), 2.12 (m, 1H), 3.20-3.60 (m, 7H), 3.60-3.70 (m, 2H), 3.90-4.0 (m, 1H), 4.42 (m, 2H), 5.0-5.1 (m, 1H), 6.15 (s, 1H, OH), 6.95-7.05 (m, 3H ), 7.10-7.22 (m, 5H), 7.25-7.40 (m, 5H), 7.57-7.65 (m, 2H).

Example 11

(3R) -3- (2-Hydroxy-3-phenyl-2-thien-2-ylpropionyloxy] -1- (3-phenoxypropyl) -1-azoniabicyclo [2.2.2] octane trifluoroacetate The title compound was synthesized as a mixture of diastereomers according to the methods d, and from intermediate 1-18 The yield of the final step was 15 mg, 52% MS [M-CF 3 COO] +: 492 1 H-NMR (DMSO- -d6): δ 1.45-1.70 (m, 1H), 1.75-2.0 (m, 3H), 2.0-2.30 (m, 3H), 3.0-3.0 17 (m, 1H), 3.17-3.57 (m, 8H), 3.80-3.90 (m, 1H), 3.97-4.10 (m, 2H), 5.22 (M, 1H), 6.52-6.60 (d, 1H, OH), 6.90-7.04 (m, 4H), 7.14-7.28 (m, 6H), 7.28-7.38 (m, 2H), 7.42-7.50 (m, 1H) *

Example 12

(3R) -3- (2-Hydroxy-3-phenyl-2-thien-2-ylpropionyloxy] -1- (3-thien-2-ylpropyl) -1-azonia-bicyclo [2.2.2] octane trifluoroacetate The title compound was synthesized as a mixture of diastereomers according to methods d, and from intermediate 1-18. The yield of the final step was 21 mg, 74%. MS [M-CF 3 COO] +: 482 1 H-NMR (DMSO-d6): δ 1.45-1.70 (m, 1H), 1.75-2.05 (m, 5H), 2.05-2.3 (m, 1H), 2.77- 2.87 (m, 2H), 2.90-3.10 (m, 3H), 3.39-3.52 (m, 1H), 6.52-6.57 (d, ), 7.37-7.47 (m), 3.75-3.82 (m, 1H, OH), 6.92-7.05 (m, 2H), 1H), 5.0-5.07 (m, (m, 3H), 7.10-7.27

Example 13

(3R) -3- (2-Hydroxy-2-thien-2-ylpent-4-enoyloxy) -1- (3-phenoxypropyl) -1-azoniabicyclo [2.2.2] octane bromide The title compound was synthesized as a mixture of diastereomers according to methods c, and from intermediate 1-3. The yield of the final step was 300 mg, 71%. MS [M-Br] +: 442, mp: 157øC (described in the experimental section, method a) 1 H-NMR (DMSO- d 6): δ 1.070-2.05 (m, 4H) (M, 1H), 2.90-3.02 (m, 1H), 3.25-3.60 (m, 7H), 3.82-3.97 (m, 1H), 3.97-4.10 (m, 2H), 5.05-5.25 (m, 3H), 5.7-10-5.90 , 1H), 6.50 (d, 1H, OH), 6.90-7.05 (m, 4H) (, 7.10-7.20 (m, 1H), 7.27-7.35 m, 2H), 7.45 (m, 1H).

Example 14

(3R) -3- (2-hydroxy-2-thien-2-ylpent-4-enoyloxy] -1- (3-thien-2-ylpropyl) -1-azoniabicyclo [2.2.2] octane trifluoroacetate 89 ΡΕ1353919 The title compound was synthesized as a mixture of diastereomers according to methods c and e from intermediate 1-3. The yield of the final step was 10 mg, 39.3%. MS [M-CF 3 COO] +: 432 1 H-NMR (DMSO-d 6): δ 1.65-2.18 (m, 6H), 2.18-2.30 (m, 1H), 2.70-3.05 (m, 4H) (M, 1H), 3.78-3.92 (m, 2H), 4.0-4.1 (m, 1H) 1H), 5.0-5.20 (m, 3H), 5.70-5.85 (m, 1H), 6.5 (d, 1H, OH), 6.90-7.7 02 (m, 3H), 7.10-7.20 (m, 1H), 7.35-7.42 (m, 1H), 7.42-7.50 (m, 1H).

Example 15

(3R) -3- (2-Hydroxy-2-thien-2-ylpent-4-enoyloxy] -1- (2-phenoxyethyl) -1-azoniabicyclo [2.2.2] octane bromide The title compound was synthesized as a mixture of diastereomers according to methods c and y from intermediate 1-3. The yield of the final step was 270 mg, 66%.

1 H-NMR (DMSO-d 6): δ 1.72-2.10 (m, 4H), 2.20-2.35 (m, 1H) (M, 1H), 2.90-3.05 (m, 1H), 3.25-3.85 (m, 7H), 3.92-4.12 (m, 1H), 4.35-4.45 (m, 2H), 4.95-5.20 (m, 3H), 5.70-5.90 (m, 1H), 6.50 (s, 1H, OH), 6.90-7.05 (m, 4H), 7.10-7.18 (m, 1H), 7.25-7.45 (m, 3H).

Example 16

(3R) -3- (2-Hydroxy-2-thien-2-yl-heptanoyloxy) -1- (3-phenoxypropyl) -1-azoniabicyclo [2.2.2] octane trifluoroacetate The title compound was synthesized as a A mixture of diastereomers according to methods c and e from intermediate 1-1. The yield of the final step was 16.2 mg, 57%. MS [M-CF 3 COO] +: 472 1H-NMR (DMSO-d6): δ0.08-0.90 (m, 3H), 1.15-1.40 (m, 6H), 1.65-2 (M, 5H), 3.85-3.95 (m, 1H), 3.95-4.10 (m, 2H), 5.05 (m, (D, 1H, OH), 6.90-7.05 (m, 4H), 7.10-7.17 (m, 1H) , 7.25-7.35 (m, 2H), 7.42-7.48 (m, 1H).

Example 17

(3R) -3- (2-Hydroxy-2-thien-2-yl-heptanoyloxy) -1- (3-thien-2-ylpropyl) -1-azoniabicyclo [2.2.2] octane trifluoroacetate The title compound was synthesized as a mixture of diastereomers according to methods c and e from intermediate 1-1. The yield of the final step was 6.8 mg, 12%. MS [M-CF 3 COO] +: 462 1H-NMR (DMSO-d6): δ0.88-0.90 (m, 3H), 1.15-1.40 (m, 6H), 1.65-2 (M, 2H), 3.10-3.55 (m, 7H), 3.75-3.90 (m, 1H), 5.10 (m, (m, 1H), 6.30-6.32 (d, 1H, OH), 6.90-6.95 (m, 1H), 6.95-7.02 (m, 2H), 7.09 -7.13 (m, 1H), 7.37-7.39 (m, 1H), 7.40-7.45 (m, 1H).

Example 18

(3R) -3- (2-Hydroxy-2-thien-2-ylpent-3-yloxy) -1- (3-phenoxypropyl) -1-azoniabicyclo [2.2.2] octane trifluoroacetate The title compound was synthesized as a mixture of diastereomers according to the methods d, and from intermediate 1-19. The yield of the final step was 6.4 mg, 12%. MS [M-CF 3 COO] +: 440 1-NMR (DMSO-d 6): δ 1.60-2.05 (m, 7H), 2.05-2.20 (m, 2H), 2.20-2 (M, 7H), 3.82-3.97 (m, 1H), 3.97-4.10 (m, 2H), 5.13 (m, 1H), 6.90-7.06 (m, 4H), 7.20-7.38 (m, 4H), 7.50-7.56 (m, 1H). 92 ΡΕ1353919

Example 19

(3R) -3- (2-hydroxy-2-thien-2-ylpent-3-yloxy) -1- (3-thien-2-ylpropyl) -1-azoniabicyclo [2.2.2] octane trifluoroacetate The compound of the title was synthesized as a mixture of diastereomers according to methods d, and from intermediate 1-19. The yield of the final step was 2.4 mg, 4.3%. MS [M-CF 3 COO] +: 430 1 H-NMR (DMSO-d 6): δ 1.60-2.10 (m, 9H), 2.20-2.35 (m, 1H), 2.75-2 , 90 (m, 2H), 3.10-3.70 (m, 7H), 3.75-3.95 (m, 1H), 5.12 (m, 1H), 6.91-7.04 (m, 3H), 7.19-7.42 (m, 3H), 7.48-7.55 (m, 1H).

Example 20

(3R) -3- (2-Hydroxy-2-thien-2-ylbut-3-enoyloxy) -1- (3-phenoxypropyl) -1-azoniabicyclo [2.2.2] octane trifluoroacetate The title compound was synthesized as a mixture of diastereomers according to methods d, and from intermediate 1-20. The yield of the final step was 9.6 mg, 16%. ΔΕ1353919 93 MS [M-CF3 COO] +: 428 1 H-NMR (DMSO-dβ): δ 1.60-2.05 (m, 4H), 2.05-2.20 (m, 2H) 20-2.38 (m, 1H), 3.15-3.60 (m, 7H), 3.82-3.95 (m, 1H), 3.98-4.10 (m, 2H), 5.10-5.20 (m, 1H), 5.25-5.35 (m, 1H), 5.45-5.55 (m, 1H), 6.45-6.55 (m, 1H ), 6.75-6.82 (d, 1H, OH), 6.92-6.96 (m, 3H), 6.98-7.03 (m, 1H), 7.13-7.15 (m, 1H), 7.28-7.34 (m, 1H), 7.48-7.52 (m, 1H).

Example 21

(3R) -3- (2-Hydroxy-2-thien-2-ylbut-3-enoyloxy) -1- (3-thien-2-ylpropyl) -1-azoniabicyclo [2.2.2] octane trifluoroacetate The compound of the title was synthesized as a mixture of diastereomers according to methods d, and from intermediate 1-20. The yield of the final step was 5.8 mg, 10%. MS [M-CF 3 COO] +: 418 1 H-NMR (DMSOd 6): δ 1.60-2.20 (m, 6H), 2.20-2.35 (m, 1H), 2.79- 2H), 3.10-3.55 (m, 7H), 3.80-3.90 (m, 1H), 5.10-5.20 (m, 1H) 25-5.35 (m, 1H), 5.45-5.55 (m, 1H), 6.45-6.55 (m, 1H), 6.75-6.78 (d, 1H, OH ), 6.92-6.95 (m, 1H), 6.05-7.05 (m, 2H), 7.10-7.15 (m, 1H), 7.35-7.42 (m, , 1H), 7.45-7.52 (m, 1H). 94 ΡΕ1353919

Example 22

(3R) -3 - [(2S) - (2-Cyclopentyl-2-hydroxy-2-thien-2-ylacetoxy] -1- (3-phenoxypropyl) -1-azoniabicyclo [2.2.2] octane bromide The title compound was synthesized according to methods d, and from intermediate I-15a. The yield of the final step was 230 mg, 85% MS [M-Br] +: 470, mp: 171 ° C. 1 H-NMR (DMSO- d 6): δ 1.27-1.67 (m, 8H), 1.8-6.05 (m, 4H), 2.05-2.20 (m, 2H) , 2.35 (m, 1H), 2.70-2.92 (m, 1H), 3.20-3.25 (m, 1H), 3.25-3.60 (m, 6H), 3.80-3.95 (m, 1H), 3.95-4.08 (m, 2H), 5.11-5.5 (m, 1H), 6.18 (s, 1H), 6.87-7.05 (m, 4H), 7.08-7.20 (m, 1H), 7.25-7.77 (m, 2H), 7.40-7.75 47 (m, 1H).

Example 23

(3R) -3 - [(2S) - (2-Cyclopentyl-2-hydroxy-2-thien-2-ylacetoxy] -1- (3-thien-2-ylpropyl) -1-azoniabicyclo [2.2.2 ] octane The title compound was synthesized according to methods d, and from intermediate I-15a. The yield of the final step was 21 mg, 75% [MS-M-CF 3 COO] +: 460-NMR (M, 8H), 1.80-2.10 (m, 6H), 2.28 (m, 1H), 2.75-2.85 (m, 3H), 3. 10-3 LO LO (m, 7H), 3.80-3.90 (m, 1H), 5.05-15.15 (m, 1H), 6.1 20 (s, 1H, OH), 6.90-6.95 (m, 1H), 6.95-7.05 (m, 2H), 7.10-7.20 (m, 1H ), 7.37-7.45 (m, 2H).

Example 24

(3R) -3 - [(2S) - (2-Cyclopentyl-2-hydroxy-2-thien-2-ylacetoxy] -1- (2-phenoxyethyl) -1-azoniabicyclo [2.2.2] octane bromide The title compound was synthesized according to methods c and y from intermediate I-15a. The yield of the final step was 338mg, 92%.

MS [M-Br] +: 456; mp: 75 ° C 1 H-NMR (DMSO-d 6): δ 1.25-1.65 (m, 8H), 1.75-2.10 (m, 4H), 2.27-2.35 , 1H), 2.70-2.90 (m, 1H), 3.30-3.68 (m, 5H), 3.68-3.83 (m, 2H), 3.92-4.10 (m, 1H), 4.32-4.50 (m, 2H), 5.10-5.20 (m, 1H), 6.20 (s, 1H, OH), 6.90-7.05 (m, 4H), 7.10-7.20 (m, 1H), 7.30-7.42 (m, 3H). 96 ΡΕ1353919

Example 25

(3R) -3 - [(2S) - (2-Cyclopentyl-2-hydroxy-2-thien-2-ylacetoxy] -1-phenethyl-1-azoniabicyclo [2.2.2] octane trifluoroacetate The title compound was synthesized as in Example 23. The yield of the final step was 17 mg, 64% MS [M-CF 3 COO] +: 440 1 H-NMR (DMSO-d 6): δ 1.30-LO (M, 1H), 2.75-2.85 (m, 1H), 2.95-3.05 (m, 2H) ), 3.20-3.50 (m, 6H), 3.50-3.65 (m, 1H), 3.85-3.95 (m, 1H), 5. 10-5.20 (m , 1H), 6.22 (s, 1H, OH), 6.95-7.05 (m, 1H), 7.10-7.20 (m, 1H), 7.20-7.40 (m, , 5H), 7.40-7.55 (m, 1H)

Example 26

(3R) -3 - [(2S) - (2-Cyclopentyl-2-hydroxy-2-thien-2-ylacetoxy] -1- (3-phenylpropyl) -1-azonia-bicyclo [2.2.2] octane trifluoroacetate The title compound was synthesized as in Example 23. The yield of the final step was 20 mg, 74% MS [M-CF3 COO] +: 454 97 ΡΕ1353919 ¹H-NMR (DMSO-d:): δ 1, 30-1.65 (m, 8H), 1.75-2.05 (m, 6H), 2.28 (m, 1H), 2.55-2.65 (m, 2H), 2.75- (M, 6H), 3.40-3.55 (m, 1H), 3.77-3.87 (m, 1H) , 5.05-5.15 (m, 1H), 6,20 (s, 1H, OH), 6.95-7.0 (m, 1H), 7.10-7.15 (m, 1H), 7.20-7.35 (m, 5H), 7.38-7.42 (m, 1H).

Example 27

(3R) -3 - [(2S) - (2-Cyclopentyl-2-hydroxy-2-thien-2-ylacetoxy] -1- (3-phenylallyl) -1-azonia-bicyclo [2.2.2] octane trifluoroacetate The title compound was synthesized as in

Example 23) The yield of the final step was 3 mg, 612 ° C MS (M + -cf3 (SOO) +: 452 ΧΗ · -RMK (DMSO-d6:): δ 1.25-1 (M, 4H), 2.31 (m, 1H), 2.72-2.85 (m, 1H), 3.12-3.22 (m, 1H), 3.22-3.45 (m, 3H), 3.45-3.60 (m, 1H), 3.83-3.92 (m, 1H) (M, 1H), 6.20 (s, 1H, OH), 6.35-6.50 (m, 1H) ), 6.82-6.95 (m, 2H), 7.10-7.15 (m, 1H), 7.25-7.77 (m, 4H), 7.55-7.62 (m, 2H).

Example 28

(3R) -3 - [(2S) - (2-Cyclopentyl-2-hydroxy-2-thien-2-ylacetoxy] -1- [3- (4-fluorophenoxy) propyl] -1-azoniabicyclo [2.2.1] 2] octane The title compound was synthesized as in Example 23. The yield of the final step was 15 mg, 52% MS [M-CF 3 COO] +: 488 1 H-NMR (DMSO- d 6) (M, 8H), 1.000 (d, 2H), 2.05 (m, 4H), 2.05-2.17 (m, 2H), 2.30 (m, , 1H), 2.75-2.90 (m, 1H), 3.17-3.27 (m, 1H), 3.27-3.60 (m, 6H), 3.82 - (M, 2H), 5.14 (m, 1H), 6.22 (s, 1H, OH), 6.92-7.05 m, 3H), 7.10-7.20 (m, 3H), 7.40-7.55 (m, 1H).

Example 29

(3R) -3 - [(2S) - (2-Cyclopentyl-2-hydroxy-2-thien-2-ylacetoxy] -1- (4-oxo-4-thien-2-ylbutyl) -1-azoniabicyclo [2.2.2] octane The title compound was synthesized as in Example 23. The yield of the final step was 4 mg, 14% MS [M-CF 3 COO] +: 488 1 H-NMR (DMSO- d 6): δ (M, 8H), 1.70-2.0 (m, 6H), 2.30 (m, 1H), 2.75-2.90 (m, 1H ), 3.05-3.12 (m 2H), 3.15-3.60 (m, 7H), 3.80-3.92 (m, 1H), 5.13 (m, 1H) (M, 1H), 7.12-7.18 (m, 1H), 7.25-7.30 (m, 1H); (M, 1H), 7.95-8.0 (m, 1H) 8.02-8.07 (m, 1H) 99 ΡΕ1353919

Example 30

(3R) -3 - [(2S) - (2-Cyclopentyl-2-hydroxy-2-thien-2-ylacetoxy] -1- [4- (4-fluorophenyl) -4-oxobutyl] -1-azoniabicyclo [2.2.2] octane The title compound was synthesized as in Example 23. The yield of the final step was 9 mg, 29% MS [M-CF 3 COO] +: 500 1 H-NMR (DMSO-d 6): δ 1.25-1.65 (m, 8H), 1.70-2.05 (m, 6H), 2.30 (m, 1H), 2.75-2.90 (m, 1H), 3. (M, 9H), 3.80-3.95 (m, 1H), 5.14 (m, 1H), 6.22 (s, 1H, OH), 6,98-7 , Δ (m, 1H), 7.12-7.20 (m, 1H), 7.35-7.45 (m, 3H), 8.02-8.12 (m, 2H).

Example 31

(3R) -3 - [(2S) - (2-Cyclopentyl-2-hydroxy-2-thien-2-ylacetoxy] -1- [3- (3-hydroxyphenoxy) propyl] -1-azoniabicyclo [2.2 The title compound was synthesized as in Example 23. The yield of the final step was 14 mg, 48% MS [M-CF 3 COO] +: 486 100 ΡΕ1353919 1 H-NMR (DMSO-d6): δ 1.25-1.65 (m, 8H), 1.80-2.0 (m, 4H), 2.0-2.20 (m, 1H), 2.30 (m, 1H) 75-2.90 (m, 1H) 3.17-3.25 (m, 1H), 3.25-3.60 (m, 6H), 3.82-3.92 (m, 1H). (M, 3H), 6.95 (s, 1H, OH), 6.30-6.42 (m, 2H) 10 (m, 2H), 7.12-7.20 (m, 1H), 7.20-7.45 (m, 1H), 9.47 (s, 1H, OH).

Example 32

1- (2-Benzyloxyethyl) - (3R) -3 - [(2S) - (2-cyclopentyl-2-hydroxy-2-thien-2-ylacetoxy] -1-azoniabicyclo [2.2.2] octane trifluoroacetate The compound of the title was synthesized as in Example 23. The yield of the final step was 10 mg, 35% MS [M-CF 3 COO] +: 470 1 H-NMR (DMSO-d 6): δ 1.25-1.62 ( m, 8H), 1.80-2.07 (m, 4H), 2.30 (m, 1H), 2.75-2.85 (m, 1H), 3.0-3.65 (m, 7H), 3.75-4.0 (m, 3H), 4.50 (s, 2H), 5.10-5.17 (m, 1H), 6.21 (s, 1H, 95-7.0 (m, 1H), 7.10-7.17 (m, 1H), 7.27-7.45 (m, 6H).

Example 33

(3R) -3 - [(2S) - (2-Cyclopentyl-2-hydroxy-2-thien-2-ylacetoxy] -1- (3-o-tolyloxypropyl) -1-azoniabicyclo [2.2.2] octane trifluoroacetate The title compound was synthesized as in Example 23. The yield of the final step was 13 mg, 45% MS [M-CF 3 COO] +: 484 1 H-NMR (DMSO-d 6): δ 1.23- (M, 4H), 2.05-2.20 (m, 5H), 2.31 (m, 1H), 2.75 (m, (M, 1H), 3.27 (s, 3H), 3.60 (m, 6H), 3.85-3.95 (m, 1H), 3.97-4.05 (m, 2H), 5.15 (m, 1H), 6.22 (s, 1H, OH), 6.83-6.93 (m, 2H), 6.98-7.02 (m, 1H), 7.12- 7.20 (m, 3H), 7.40-7.46 (m, 1H).

Example 34

1- [3- (3-Cyanophenoxy) propyl] - (3R) -3 - [(2S) - (2-cyclopentyl-2-hydroxy-2-thien-2-ylacetoxy] -1-azoniabicyclo [2.2.1] 2] octane The title compound was synthesized as in Example 23. The yield of the final step was 11 mg, 32% MS [M-CF3 COO] +: 495 1H-NMR (DMSO-d6): δ 1.25 (M, 2H), 2.30 (m, 1H), 2.75 (m, 2H), 2.75 (m, 2.90 (m, 1H), Î'20-3.25 (m, 1H), 3.25-3.60 (m, 6H), 3.82-3.95 (m, 1H) 05-4.15 (m, 2H), 5.07-5.20 (m, 1H), 6.20 (s, 1H, OH), 6.95-7.05 (m, 1H), 7 , 12-7.20 (m, 1H), 7.25-7.35 (m, 3H), 7.40-7.57 (m, 4H) 102 ΡΕ1353919

Example 35

(3R) -3 - [(2S) - (2-Cyclopentyl-2-hydroxy-2-thien-2-ylacetoxy] -1- [3- (naphthalen-1-yloxy) pro-pyl] -1- azoniabicyclo [2.2.2] octane The title compound was synthesized as in Example 23. The yield of the final step was 10 mg, 26%. MS [M-CF 3 COO] +: 520, (described in the experimental section, method b ) (m, (m, (m, 1H), 1H) .1 H-NMR (DMSO-d6): δ 1.30-1.65 (m, 8H), 1.80-2.10 (4H), 2 (M, 1H), 3.30-3.65 (m, 1H), 3.90-4.05 (m, 1H) 15.4.30 (m, 2H), 5.15-5.22 (1H), 6.24 (s, 1H, OH), 6.95-7.05 (m, 2H), 7.15-7 , 20 (m, 7.40-7.60 (m, 5H), 7.85-7.95 (m, 1H), 8.20-8.25 (m,

Example 36

(3R) -3 - [(2S) - (2-Cyclopentyl-2-hydroxy-2-thien-2-ylacetoxy] -1- [3- (methylphenylamino) propyl] -1-azoniabicyclo [2.2.2 ] octane The title compound was synthesized as in Example 23. The yield of the final step was 12 mg, 35% MS [M-CF3 COO] +: 483 103 ΡΕ1353919 1 H-NMR (DMSO-d6): δ 1 (M, 6H), 2.28 (m, 1H), 2.75-2.85 (m, 1H), 1.75 (m, , 2.87 (s, 3H), 3.09-3.14 (m, 1H), 3.15-3.55 (m, 8H), 3.75-3.87 (m, 1H ), 5.05-5.15 (m, 1H), 6,20 (s, 1H, OH), 6.60-6.70 (m, X-6, 70-6.77 (m, 2H), 6.92-8.07 (m, 1H), 7.10-7.25 (m, 3H), 7.37-7.45 (m, 1H).

Example 37

(3R) -3 - [(2S) - (2-Cyclopentyl-2-hydroxy-2-thien-2-ylacetoxy] -1- (3-phenylsulfanylpropyl) -1-azoniabicyclo [2.2.2] octane trifluoroacetate The compound of the title compound was synthesized as in Example 23. The yield of the final step was 7 mg, 22% MS [M-CF 3 COO] +: 486 1 H-NMR (DMSO-d 6): δ 1.25-1.65 (m, 8H); 1.75-2.02 (m, 6H); 2.27 (m, 1H), 2.75-2.90 (m, 1H), 2.95-3.05 m, 2H), 3.07-3.15 (m, 1H), 3.15-3.52 (m, 6H), 7.75-3.87 (m, 1H), 5.05 (M, 1H), 6.95-7.0 (m, 1H), 7.12-7.77 (m, 1H) 20-7.30 (m, 1H), 7.30-7.45 (m, 5H)

Example 38

(3R) -3 - [(2S) - (2-Cyclopentyl-2-hydroxy-2-thien-2-ylacetoxy] -1- (4-oxo-4-phenylbutyl) -1-azoniabicyclo [2.2.2 ] octane The title compound was synthesized as in Example 23. The yield of the final step was 9 mg, 26% MS [M-CF 3 COO] +: 482 1 H-NMR (DMSO-d 6): δ 1, (M, 8H), 1.72-2.10 (m, 6H), 2.30 (m, 1H), 2.75-2.90 (m, 1H), 3.10- 3.60 (m, 9H), 3.85-3.95 (m, 1H), 5.10-5.20 (m, 1H), 6.23 (s, 1H, OH), 6.95- 7.05 (m, 1H), 7.12-7.20 (m, 1H), 7.40-7.47 (m, 1H), 7.52-7.60 (m, 2)

(3R) -3 - [(2S) - (2-Cyclopentyl-2-hydroxy-2-thien-2-ylacetoxy] -1- [3- (2,4,6-trimethylphenoxy) -propyl] -1- -azoniabicyclo [2.2.2] octane The title compound was synthesized as in Example 23. The yield of the final step was 13 mg, 35%. MS [M-CF 3 COO] +: 512 1 H-NMR (DMSOd 6; ): δ 1.30-LO co -1 (m, 8H), 1.000 (m, 4H), 2.02-2.25 (m, 11H), 2.32 (m, m, 1H), 2.75-2.90 (m, 1H), 3.23-3.28 (m, 1H), 3.28-3.62 (m, 6H), 3.65- (M, 1H), 5.10 (m, 2H), 3.85-3.97 (m, 1H), 5.10 (S, 2H), 6.97-7.05 (m, 1H), 7.12-7.20 (m, 1H), 7.40-7.47 (m, 1H) 105 ΡΕ1353919

Example 40

1- [3- (2-Chlorophenoxy) propyl] - (3R) -3 - [(2S) - (2-cyclopentyl-2-hydroxy-2-thien-2-ylacetoxy] -1-azoniabicyclo [2.2 .2] octane The title compound was synthesized as in Example 23. The yield of the final step was 13 mg, 36% MS [M-CF 3 COO] +: 505 1 H-NMR (DMSO-d 6): δ 1, (M, 8H), 1.75-2.05 (m, 4H), 2.05-2.25 (m, 2H), 2.31 (m, 1H), 2.75 = 2.90 (m, 1H), 3.19-3.23 (m, 1H), 3.23-3.62 (m, 6H), 3.85-4.0 (m, (M, 2H), 7.92 (s, 1H, OH), 6.92-7.05 (m, 2H), 7.04 , 12-7.22 (m, 2H), 7.27-7.37 (m, 1H), 7.40-7.50 (m, 2H).

Example 41

(3R) -3 - [(2S) - (2-Cyclopentyl-2-hydroxy-2-thien-2-ylacetoxy] -1- [3- (3-trifluoromethylphenyl) propyl] -1- azoniabicyclo [ 2.2.2] octane The title compound was synthesized as in Example 23. The yield of the final step was 13 mg, 33%. MS [M-CF 3 COO] +: 538 ΧΗ-NMR (DMSO- d 6) : δ 1.15 (LO) (m, 8H), 1.75-2.0 (m, 4H), 2.05-2.25 (m, 2H), 2.31 (m, 1H ), 2.75-2.90 (1H, m), 3.20-3.25 (m, 1H), 3.25-3.62 (m, 6H), 3.82-3.95 (m, 1H), 4.05-4.20 (m, 2H), 5.10-5.20 (m, 1H), 6.22 (s, 1H OH), 6.10-7.05 (m, 1H), 7.12-7.20 (m, 1H), 7.22-7.30 (m 2H), 7.79-7.37 (m, 1H), 7.40 (M, 1H), 7.50-7.62 (m, 1H).

Example 42

1- [3- (biphenyl-4-yloxy) proyl] - (3R) -3 - [(2S) - (2-cyclopentyl-2-hydroxy-2-thien-2-ylacetoxy] -1-azoniabicyclo [ 2.2.2] octane The title compound was synthesized as in Example 23. The yield of the final step was 11 mg, 30% MS [M-CF 3 COO] +: 546 1 H-NMR (DMSO-d 6): δ 1 , 15-LO-1 (m, 8H), 1.77-2.05 (m, 4H), 2.05-2.25 (m, 2H), 2.31 (m, 1H), 2. (M, 1H), 3.23-3.62 (m, 6H), 3.85-3.97 (m, 1H) , 4.05 (s, 1H, OH), 6.95-7.10 (m, 3H), 4.05 (m, 2H) , 7.72-7.20 (m, 1H), 7.27-7.37 (m, 1H), 7.40-7.50 (m, 3H), 7.55-7.70 (m, 4H), 107 ΡΕ1353919

Example 43

(3R) -3 - [(2S) - (2-Cyclopentyl-2-hydroxy-2-thien-2-ylacetoxy] -1- [3- (2,4-difluorooxy) pro-yl] -1- azoniabicyclo [2.2.2] octane The title compound was synthesized as in Example 23. The yield of the final step was 10 mg, 28%. MS [M-CF 3 COO] +: 506 1 H-NMR (DMSO- d 6): (m, 8H), 1.75-2.05 (m, 4H), 2.05-2.15 (m, 2H) 2.30 (m, 1H) , 2.82 (m, 1H), 3.17-3.28 (m, 1H), 3.28-3.47 (m, 5H), 3.47-3.60 (m, 1H), 3. (M, 2H), 5.14 (m, 1H), 6.22 (s, 1H, OH), 6.95-7.0 , 10 (m, 2H), 7.12- 7.38 (m, 3H), 7.40-7.45 (m, 1H).

Example 44

(3R) -3 - [(2S) - (2-Cyclopentyl-2-hydroxy-2-thien-2-ylacetoxy] -1- [3- (4-methoxyphenoxy) propyl] -1-azoniabicyclo [2.2.1] 2] octane The title compound was synthesized as in Example 23. The yield of the final step was 11 mg, 32% MS [M-CF3 COO] +: 500 108 ΡΕ1353919 1 H-NMR (DMSO-d6): δ 1 , 25-1.65 (m, 8H), 1.75-2.15 (m, 6H), 2.30 (m, 1H), 2.82 (m, 1H), 3.18-3.25 (m, 1H), 3.25-3.45 (m, 5H), 3.445-3.60 (m, 1H), 3.70 (s, 3H), 3.82-3.92 (m, 1H (M, 2H), 5.14 (m, 1H), 6.22 (s, 1H, OH), 6.88 (m, 4H), 6.98-7.70 (M, 1H), 7.15-7.16 (m, 1H), 7.42-7.44 (m, 1H).

Example 45

(3R) -3 - [(2S) - (2-Cyclopentyl-2-hydroxy-2-thien-2-ylacetoxy] -1- [3- (5,6,7,8-tetrahydronaphthalen-2 yloxy) propyl] -1-azoniabicyclo [2.2.2] octane The title compound was synthesized as in Example 23. The yield of the final step was 14 mg, 38% MS [M-CF 3 COO] +: 524 1H 1 H-NMR (DMSO-d 6): δ 1.30 - 1.65 (m, 8H); 1.65 - 1.75 (m, 4H); 1.75 - 2.20 (m, 6H); 2.30 (m, 4H), 2.75-2.95 (m, 1H), 3.17-3.25 (m, 1H), 2.70 3.45 (m, 5H), 3.45-3.60 (m, 1H), 3.80-3.92 (m, 1H), 3.92-4.02 m, 2H), 5.14 (m, 1H), 6.22 (s, 1H, OH), 6.60-6.70 (m, 2H), 6.95-7.02 (m, 1H ), 7.15-7.20 (m, 1H), 7.21-7.45 (m, 1H) and

Example 46

1- [3- (Benzo [1,3] dioxol-5-yloxy) propyl] - (3R) -3 - [(2S) - (2-cyclopentyl-2-hydroxy-2-thien-2-ylacetoxy ] -1-azoniabicyclo [2.2.2] octane The title compound was synthesized as in Example 23. The yield of the final step was 13 mg, 38% MS [M-CF 3 COO] +: 514-NMR (M, 8H), 1.75-2.15 (m, 6H), 2.30 (m, 1H), 2.75 (d, (M, 1H), 3.25-3.42 (m, 5H), 3.42-3.60 (m, 1H) 1H), 3.82-3.92 (m, 1H), 3.92-4. 0 (m, 2H9, 5.13 (m, 1H), 5.97 (s, 2H), 6,20 (s, 1H, OH); 6.36 and 5.40 (m, 1H); 6.64 (m, 1H), 6.81-6.84 (m, 1H); , 98-7.02 (m, 1H), 7.15-7.17 (m, 1H), 7.42-7.45 (m, 1H).

Example 47

1- [3- (2-Carbamoylphenoxy) pro-yl] - (3R) -3 - [(2S) - (2-cyclopentyl-2-hydroxy-2-thien-2-ylacetoxy] -1-azoniabicyclo [ 2.2.2] octane The title compound was synthesized as in Example 23. The yield of the final step was 13 mg, 36% MS [M-CF 3 COO] +: 513 1 H-NMR (DMSO-d 6): δ 1 , 27-1.65 (m, 8H), 1.80-2.07 (m, 4H), 2.12-2.27 (m, 2H), 2.31 (m, 1H), 2.82 (m, 1H), 3.17-3.25 (m, 1H), 3.25-3.45 (m, 5H), 3.45-3.60m, 1H), 3.82-3, (M, 2H), 5.15 (m, 1H), 6.23 (s, 1H, OH), 6.98-7.16 (m, 1H). m, 4H), 7.24-7.50 (m, 2H), 7.50-7.55 (m, 2H), 7.68-7.72 (m, 1H).

Example 48

(3R) -3 - [(2S) - (2-Cyclopentyl-2-hydroxy-2-thien-2-ylacetoxy] -1- [3- (3-dimethylaminophenoxy) -propyl] -1-azoniabicyclo [2.2 .2] octane The title compound was synthesized as in Example 23. The yield of the final step was 14 mg, 40% MS [M-CF 3 COO] +: 513 1 H-NMR (DMSO-d 6): δ 1, 25-1.65 (m, 8H), 1.70-2.20 (m, 6H), 2.30 (m, 1H), 2.75-2.95 (m, 7H), 3.15- 3.65 (m, 7H), 3.80-4.05 (m, 3H), 5.14 (m, 1H), 6.15-6.30 (m, 3H), 6.32-6, 36 (m, 1H), 6.95-7.22 (m, 3H), 7.40-7.45 (m, 1H).

Example 49

1- [3- (4-Acetylaminophenoxy) propyl] - (3R) -3 - [(2S) - (2-cyclopentyl-2-hydroxy-2-thien-2-ylacetoxy] -1-azoniabicyclo [2.2 The title compound was synthesized as in Example 23. The yield of the final step was 12 mg, 34% MS [M-CF 3 COO] +: 527 111 ΡΕ1353919 1 H-NMR (DMSO-d6) : δ 1.25 LO -1 -1 (m, 8H), 1.75-2.20 (m, 9H), 2.30 (m, 1H), 2.82 (m, 1H), 3.17 -3.28 (m, 1H), 3.28-3.45 (m, 5H), 3.45-3.60 (m, 1H), 3.84-3.92 (m, 1H), (M, 2H), 6.10 (m, 2H), 6.86 (m, 2H), 5.13 98 - 7.02 (m, 1H), 7.15-7.17 (m, 1H), 7.42-7.45 (m, 1H), 7.48-7.52 (m, 2H), 9 , 85 (s, 1H, NH (CO)).

Example 50

(3R) -3 - [(2S) - (2-Cyclopentyl-2-hydroxy-2-thien-2-ylacetoxy] -1- [3- (4-methoxycarbonylphenoxy) propyl] -1-azoniabicyclo [ 2.2.2] octane The title compound was synthesized as in Example 23. The yield of the final step was 14 mg, 37%. MS [M-CF 3 COO] +: 528 1H-NMR (DMSO-d (5): δ 1.25-1.60 (m, 8H), 1.80-2.05 (m, 4H), 2.05-2.25 (m, 1H), 2.82 (m, 1H), (M, 1H), 3.28-3.45 (m, 5H), 3.45-3.60 (m, (M, 2H), 5.14 (m, 1H), 6.22 (s, 1H, OH), 6.95-7.49 (m, 10 (m, 3H), 7.15-7.17 (m, 1H), 7.43-7.45 (m, 1H), 7.92-7.97 (m, 2H).

Example 51

(3R) -3 - [(2S) - (2-Cyclopentyl-2-hydroxy-2-thien-2-ylacetoxy] -1- [3- (4-nitrophenoxy) propyl] -1-azoniabicyclo [2.2.1] 2] octane The title compound was synthesized as in Example 23. The yield of the final step was 15 mg, 41% MS [M-CF 3 COO] +: 515 1 H-NMR (DMSO-d 6): δ 1.27 LO LO-1 (m, 8H), 1.77-2.07 (m, 4H), 2.10-2.27 (m, 2H) 2.31 (m, 1H), (M, 1H), 3.82-3.50 (m, 5H), 3.82-3.60 (m, 1H), 3.82-3.60 (m, (M, 1H), 6.15 (m, 1H), 6.15 (m, 1H), 4.15-4.25 02 (m, 1H), 7.14-7.18 (m, 3H), 7.42-7.45 (m, 1H), 8.22-8.27 (m, 2H).

Example 52

(3R) -3 - [(2S) - (2-Cyclopentyl-2-hydroxy-2-thien-2-ylacetoxy] -1- [3- (4-hydroxymethylphenoxy) propyl] -1-azoniabicyclo [2.2 2] octane The title compound was synthesized as in

Example 23. The yield of the final product was: 13 mg, 36%. MS [M-CF 3 COO] +: 50 1 H-NMR (DMSO-d 6): δ 1.25-1.65 (m, 8H); 1.77-2.0! (m, 4H), 2.05-2.20 (m, 2H), 2.30 (m, 1H), 2.82 (m, 1H) 3.17-3.60 (m, 7H) (M, 2H), 4.35-4.45 (m, 2H), 5.05-5.11 (t, 1H, OH), 5.11-5.20 (m 1H), 6.22 (s, 1H, OH), 6, 86-6, 95 (m, 2H), 6.95-7.05 (m, 113 ΡΕ1353919 1Η), 7.15-7.17 (m, 1H), 7.22-7.26 (m, 2H), 7.42-7.44 (m, 1H).

Example 53

(3R) -3 - [(2R) - (2-Cyclopentyl-2-hydroxy-2-thien-2-ylacetoxy] -1- (3-phenoxypropyl) -1-azoniabicyclo [2.2.2] octane bromide The title compound was synthesized according to methods d, and from intermediate I-15b. The yield of the final step was 1.2 g (73%) mp: 181 DEG C. MS [M-Br] +: 470 1 H-NMR (DMSO-d6): δ 1.30-1.70 (m, 8H), 1.70-1.80 (m, 2H), 1.80-2.05 (m, 2H) , 2.05-2.30 (m, 3H), 2.80-2.95 (m, 1H), 3.25-3.62 (m, 7H), 3.87-4.0 , 1H), 4.0-4.10 (m, 2H), 5.10-5.20 (m, 1H), 6.20 (s, 1H, OH), 6.95-7.05 (m, 4H), 7.15-7.25 (m, 1H), 7.25-7.37 (m, 2H), 7.42-7.45 (m, 1H).

Example 54

(3R) -3 - [(2R) - (2-Cyclopentyl-2-hydroxy-2-thien-2-ylacetoxy] -1- (3-thien-2-ylpropyl) -1-azoniabicyclo [2.2.2 ] octane hydrochloride The title compound was synthesized according to 114 Ρ AND 13393919 with the methods d, e from intermediate I-15b. The yield of the final step was 15 mg (54%) MS [M-CF 3 COO] +: 460-NMR (M, 8H), 1.65-1.8 (m, 2H), 1.80-2.10 (m, 4H), 2.25 (m, 2H) 21 (m, 1H), 2.77-2.90 (m 3H), 3.15-3.40 (m, 6H), 3.40-3 LO (m, 1H) (M, 1H), 6,20 (s, 1H, OH), 6,92-6,96 (m, 1H), 6 (M, 1H), 7.36-7.74 (m, 1H), 7.40-7.56 (m, 1H) 1H).

Example 55

(3R) -3 - [(2R) - (2-Cyclopentyl-2-hydroxy-2-thien-2-ylacetoxy] -1- (2-phenoxyethyl) -1-azonia-bicyclo [2.2.2] octane trifluoroacetate The title compound was synthesized as in Example 54. The yield of the final step was 16 mg, 58%. MS [M-CF 3 COO] +: 456 1 H-NMR (DMSO-d 6): δ 1.30 (M, 2H), 1.85 (m, 2H), 2.75 (m, 2H), 2.23 (m, 1H), 2.75 - 2.90 (m, 1H), 3.40-3.57 (m, 4H), 3.57-3.70 (m, 1H), 3.70-3.0 , 2H), 3.97 (s, 1H), 4.37-4.47 (m, 2H), 5.10-5.18 (m, 1H) 20 (s, 1H, OH), 6.92-7.05 (m, 4H), 7.10-7.18 (m, 1H), 7.30-7.38 (m, 2H), 7.38-7.44 (m, 1H) 115 ΡΕ1353919

Example 56

(3R) -3 - [(2R) - (2-Cyclopentyl-2-hydroxy-2-thien-2-ylacetoxy] -1-phenethyl-1-azoniabicyclo [2.2.2] octane trifluoroacetate The title compound was synthesized as in Example 54. The yield of the final step was 13 mg, 50% MS [M-CF 3 COO] +: 440 1 H-NMR (DMSO-d 6): δ 1.35-1.65 (m, 8H ), 1.65-1.85 (m, 2H), 1.85-2.05 (m, 2H), 2.25 (m, 1H), 2.85-2.92 (m, 1H), 2.95 (m, 2H), 3.30-3.50 (m, 6H), 3.50-3.65 (m, 1H), 3.85-4.0 (m, 1H), 6.22-5.20 (m, 1H), 6.21 (s, 1H, OH), 6.95-7.05 (m, 1H), 7.15-7.20 (m, 1H), 7.25-7.40 (m, 5H), 7.40-7.47 (m, 1H).

Example 57

(3R) -3 - [(2R) - (2-cyclopentyl-2-hydroxy-2-thien-2-ylacetoxy] -1- (3-phenylpropyl) -1-azonia-bicyclo [2.2.2] octane trifluoroacetate The title compound was synthesized as in Example 54. The yield of the final step was 14 mg, 53%. MS [M-CF 3 COO] +: 454 116 ΡΕ1353919-NMR (DMSO-d6): δ 1.30 (M, 8H); 1.65-1.7 (m, 2H); 1.77-2.05 (m, 4H); 2.21 (s, 1H), 2.55-2 (M, 1H), 3.15-3.34 (m, 6H), 3.40-3.05 (m, 1H) 80-3.90 (m, 1H), 5.06-5.16 (m, 1H), 6.19 (s, 1H OH), 6.95-7.02 (m, 1H), 7.7-7.18 (m, 1H), 7, 20-6, 36 (m, 5H), 7.38-7.66 (m, 1H).

Example 58

(3R) -3 - [(2R) - (2-Cyclopentyl-2-hydroxy-2-thien-2-ylacetoxy] -1- (3-phenylallyl) -1-azonia-bicyclo [2.2.2] octane trifluoroacetate The title compound was synthesized as in Example 54. The yield of the final step was 7 mg, 26% MS [M-CF 3 COO] +: 452 1 H-NMR (DMSOd 6): δ 1.30 - LO (M, 8H), 1.75-2.05 (m, 4H), 2.24 (m, 1H), 2.75-2.90 (m, 1H), 3.25-3, (M, 4H), 3.45-3.55 (m, 1H), 3.72-3.95 (m, 1H), 4.0-4.15 (m, 2H), 5.10- 5.17 (m, 1H), 6.19 (s, 1H, OH), 6.40-6.55 (m, 1H), 6.82-6.70 (m, 2H), 7.12- 7.17 (m, 1H), 7.30-7.45 (m, 4H), 7.55-7.62 (m, 2H).

Example 59

(3R) -3 - [(2R) - (2-Cyclopentyl-1α, 3β, 13β, 3β-hydroxy-2-thien-2-ylacetoxy] -1- [3- (4-fluorophenoxy) propyl] -1-azoniabicyclo [ 2.2.2] octane The title compound was synthesized as in Example 54. The yield of the final step was 19 mg, 64% MS [M-CF 3 COO] +: 488 1 H-NMR (DMSO-d 6): δ 1 (M, 2H), 1.80-2.05 (m, 2H), 2.05-2.20 (m, 2H), 2.05-2.20 (m, 2H) , 2.23 (m, 1H), 2.80-1.95 (m, 1H), 3.20-3.60 (m, 7H), 3.85-3.95 (m, 1H), 3.97 -4.07 (m, 2H), 5.14 (m, 1H), 6.20 (s, 1H, OH), 6.90-7.05 (m, 3H), 7.10-7.20 (m, m, 3H), 7.40-7.47 (m, 1H).

Example 60

(3R) -3 - [(2S) - (2-Cyclopentyl-2-fur-2-yl-2-hydroxyacetoxy] -1- (3-phenoxypropyl) -1-azoniabicyclo [2.2.2] octane trifluoroacetate The compound of title was synthesized according to methods d and from intermediate I-14a The yield of the final step was 4 mg, 15% MS [M-CF 3 COO] +: 454 1 H-NMR (DMSO-d 6): δ 1.45-1.67 (m, 9H), 1.67-1.80 (m, 1H), 1.80-2.05 (m, 2H), 2.05-2.22 (m, 3H), 2.85-2.95 (m, 1H), 3.20-3.55 (m, 7H), 3.85-3.95 (m, 1H), 3.97-4.07 (M, 1H), 6.20 (s, 1H, OH), 6.90-7.05 (m, 3H), 7.10-7.20 (m, 3H), 7.40-7.47 (m, 1H).

Example 61

(3R) -3 - [(2S) -2-Cyclopentyl-2-fur-2-yl-2-hydroxyacetoxy] -1- (3-thien-2-ylpropyl) -1-azonia-bicyclo [2.2.1] 2] octane The title compound was synthesized as in Example 60. The yield of the final step was 2 mg, 7%. MS [M-CF 3 COO] +: 444 1 H-NMR (DMSO-d 6): δ 1.40-1.66 (m, 9H), 1.66-2.10H), 2.17 (m, 1H) , 2.78-2.90 (m, 3H), 3.14-3.50 (m, 3.80-4.90 (m, 1H), 5.10-5.18 (m, 1H), 6.02 (s, 1H), -6.46 (m, 2H), 6.92-7.02 (m, 2H), 7.36-7.40 (m, 1H), 7.60 (m , 1H).

Example 62

(3R) -3 - [(2S) -2-Cyclopentyl-2-fur-2-yl-2-hydroxyacetoxy] -1-phenethyl-1-azoniabicyclo [2.2.2] octane trifluoroacetate The title compound was synthesized as in Example 60. The yield of the final step was 4 mg, 17%. Δ E1353919 119 MS [M-CF3 COO] +: 424 1 H-NMR (DMSO-d6): δ 1.40-2.05 (m, 12H), 2.20 (m, (M, 3H), 3.20-3.60 (m, 7H), LO-O = 3.95 (m, 1H), 5.18 (m, 1H), 6 , Δ (s, 1H, OH), 6.40-6.45 (m, 2H), 7.25-7.40 (m, 5H), 7.62 (m, 1H).

Example 63

(3R) -3 - [(2S) -2-cyclopentyl-2-fur-2-yl-2-hydroxyacetoxy] -1- (3-phenylpropyl) -1-azonia-bicyclo [2.2.2] octane trifluoroacetate The title compound was synthesized as in Example 60. The yield of the final step was 10 mg, 36.2%. MS [M-CF 3 COO] +: 438 1 H-NMR (DMSOd 6): δ 1.35-2.05 (m, 14H), 2.16 (m, 1H), 2.55-2.65 (m , 2H), 2.75-2.95 (m, 1H), 3.10-3.55 (m, 7H), 3.77-3.92 (m, 1H), 5.05-5.15 (m, 1H), 6.02 (S, 1h, oh), 6.35-6.45 (m, 2H), 7.17-7.40 (m, 5H), 7.60 (m, 1H ).

Example 64

(3R) -3 - [(2R) -2-cyclopentyl-2-fur-2-yl-2-hydroxyacetoxy] -1- (3-phenoxypropyl) -1-azonia-bicyclo [2.2.2] octane trifluoroacetate 120 The title compound was synthesized according to methods d, and from intermediate I-14b. The yield of the final step was 12 mg, 46%. MS [M-CF 3 COO] +: 454-NMR (DMSO-d 6): δ 1.40-1.60 (m, 8H); 1.75-2.0! (m, 4H), 2.05-2.20 (m, 2H), 2.30 (m, 1H), 2.75-2.87 (m, 1H), 3.10-3.60 (M, 1H), 3.97 (m, 1H), 3.85 (m, 1H) 1H), 6.40-6.50 (m, 2H), 6.90-7.0 (m, 3H), 7.27-7.37 (m, 2H), 7.60-7.65 (m, , 1H).

Example 65

(3R) -3 - [(2R) -2-Cyclopentyl-2-fur-2-yl-2-hydroxyacetoxy] -1- (3-thien-2-ylpropyl) -1-azonia-bicyclo [2.2.1] 2] octane The title compound was synthesized as in Example 64. The yield of the final step was 14 mg, 55%. MS [M-CF 3 COO] +: 444 1 H-NMR (DMSOd 6): δ 140 -1.65 (m, 8H), 1.75-2.1 (m, 6H), 2.27 (m, 1H ), 2.70-2.90 (m, 3H), 3.0-3.55 (m, 7H) 3.77-3.82 (m, 1H), 5.0-5.15 (m 1H), 6.03 (s, 1H), 6.40-6.45 (m, 2H), 6.90-7.05 (m, 2H), 7.35-7.42 (m, 1H ), 7.55-7.65 (m, 1H). 121 ΡΕ1353919

Example 66

(3R) -3 - [(2R) -2-cyclopentyl-2-fur-2-yl-2-hydroxyacetoxy] -1-phenethyl-1-azoniabicyclo [2.2.2] octane trifluoroacetate The title compound was synthesized as in Example 64. The yield of the final step was 15 mg, 57%. MS [M-CF 3 COO] +: 424 1H-NMR (DMSO-d6): δ 1.30-2.40 (m, 13H), 2.75-2.85 (m, 1H), 2.95-3 (M, 2H), 3.10-3.75 (m, 7H), 3.85-4.0 (m, 1H), 5.05-5.15 (m, 1H), 6.02 (s, 1H, OH), 6.44 (m, 2H), 7.20-7.40 (m, 5H), 7.63 (m, 1H).

Example 67

(3R) -3 - [(2R) -2-cyclopentyl-2-fur-2-yl-2-hydroxyacetoxy] -1- (3-phenylpropyl) -1-azoniabicyclo [2.2.2] octane trifluoroacetate The title compound was synthesized as in Example 64. The yield of the final step was 10 mg, 38%. MS [M-CF 3 COO] +: 438 1H-NMR (DMSO-d6): δ 1.40-1.60 (m, 8H), 1.75-2.05 122 ΡΕ1353919 (m, 6H), 2.27 (m, 1H), 2.55-1.60 (m, 2H), 2.79 (m, 1H) 3.00-3.10 (m, 1H), 3.12-3.40 (S, 1H, OH), 4.02 (m, 1H), 3.40-3.55 (m, 1H), 3.80-3.90 (m, 1H) , 6.40 (m 2 Η), 7.20-7.35 (m, 5H), 7.58 (m, 1H).

Example 68

(3R) -3 - [(2R) -2-cyclohexyl-2-hydroxy-2-phenylacetoxy] -1- (3-phenoxypropyl) -1-azoniabicyclo [2.2.2] octane trifluoroacetate. The title compound was synthesized according to methods d, and from intermediate I-16a. The yield of the final step was 28 mg, 100%. MS [M-CF 3 COO] +: 478. 1 H-NMR (DMSO-d 6): δ 0.95-1.18 (m, 4H), 1.18-1.65 (m, 5H), 1.70- 2.05 (m, 2H), 2.17-2.30 (m, 2H), 3.15-3.25 (m, 1H) (M, 6H), 3.75-3.90 (m, 1H), 3.95-4.07 (m, 2H), 5.05-5.15 (m, 1H). (M, 3H), 7.25-7.45 (m, 5H), 7.55-7.65 (m, 2H)

Example 69

(3R) -3 - [(2R) -2-cyclohexyl-2-hydroxy-2-phenylacetoxy] -1- (3-thien-2-ylpropyl) -1-azonia-bicyclo [2.2.2] octane The title compound was synthesized as in

Example 68. The yield of the final step was 22 mg, 78%. MS [M-CF 3 COO] + # 468. 1 H-NMR (DMSO-d 6:): δ0.95-1.18 (m, 4H), 1.18-1.65 (m, 5H), 1.70-2.0 (m, 7H), 2.20 (m, 2H); 2.75-2.85 (m, 2H), 3.05-3.15 (m, 1H), 3.15-3.50 (m, 6H), 3.70-3.85 (m, 1H ), 5.05-5.15 (m, 1H), 5.76 (s, 1H, OH), 6.90-7.05 (m, 2H), 7.20-7.45 (m, 4H ), 7.55-7.65 (m, 2H).

Example 70

(3R) -3 - [(2R) -2-cyclohexyl-2-hydroxy-2-phenylacetoxy] -1-phenethyl-1-azoniabicyclo [2.2.2] octane trifluoroacetate The title compound was synthesized as in Example 68. The yield of the final step was 14 mg, 50%. MS [M-CF 3 COO] +: 448. 1 H-NMR (DMSO-d 6): δ 0.97-1.1 (m, 3H), 1.15-2.05 (m, 11H ), 2.15-2.30 (m, 2H), 2.90-3.05 (m, 2H), 3.20-3.30 (m, 1H), 3.30-3.50 (m, 5H), 3.50-3.62 (m, 1H), 3.82-3.92 (m, 1H); 5.15 (m, 1H), 5.78 (s, 1H, OH), 7.25-7.45 (m, 8H), 7.58-7.64 (m, 2H). 124 ΡΕ1353919

Example 71

(3R) -3 - [(2S) -2-Cyclohexyl-2-hydroxy-2-phenylacetoxy] -1- (3-phenoxypropyl) -1-azoniabicyclo [2.2.2] octane trifluoroacetate The title compound was synthesized according to methods d, e from intermediate I-16b. The yield of the final step was 18 mg, 63%. MS [M-CF 3 COO] +: 478. 1 H-NMR (DMSO-d 6): δ 0.95-1.17 (m, 4H), 1.20-2.0 (m, 10H), 2.02 2.35 (m, 4H), 3.15-3.55 (m, 7H), 3.80-3.90 (m, 1H), 3.97-4.10 (m, 2H) (S, 1H, OH), 6.90-7.02 (m, 3H), 7.25-7.45 (m, 5H) 57-7.67 (m, 2H).

Example 72

(3R) -3 - [(2S) -2-cyclohexyl-2-hydroxy-2-phenylacetoxy] -1- (3-thien-2-ylpropyl) -1-azoniabicyclo [2.2.2] octane The title compound was synthesized as in Example 71. The yield of the final step was 19 mg, 66%. 1 H-NMR (DMSO-d 6): δ 0.95-1.17 (m, 4H), 1.20-2.10 (m, 12H) 15-2.35 (m, 2H), 2.75-2.97 (m, 2H), 3.10-3.37 (m, 6H), 3.37-3.55 (m, 1H), 3.75-3.87 (m, 1H), 5.05-5.12 (m, 1H), 5.74 (s, 1H, OH), 6.90-7.05 (m, 2H), 7.22-7.45 (m, 4H), 7.55-7.67 (m, 2H).

Example 73

(3R) -3 - [(2S) -2-Cyclohexyl-2-hydroxy-2-phenylacetoxy] -1-phenethyl-1-azoniabicyclo [2.2.2] octane trifluoroacetate The title compound was synthesized as in Example 71. The yield of the final step was 16 mg, 58%. MS [M-CF 3 COO] +: 448. 1 H-NMR (DMSO-d 6): δ 0.98-1.15 (m, 3H), 1.20-2.05 (m, 11H), 2.20- 2H), 2.90-3.10 (m, 2H), 3.20-3.50 (m, 6H), 3.50-3.60 (m, 1H) 80-3.92 (m, 1H), 5.12 (m, 1H), 5.75 (s, 1H, OH), 7.25-6.40 (m, 8H), 7.60-7 , 65 (m, 1H).

Example 74

(3R) -3 - [(2S) -2-cyclohexyl-2-fur-2-yl-2-hydroxyacetoxy] -1- (3-phenoxypropyl) -1-azonia-bicyclo [2.2.2] octane The title compound was synthesized according to methods c, from intermediate I-4a. The yield of the final step was 3.8 mg, 6.2%. MS [M-CF 3 COO] +: 468. 1 H-NMR (DMSO-d 6): δ 1.0-1.50 (m, 7H), 1.50-2.05 (m, 7H) (M, 4H), 3.15-3.65 (m, 4H), 3.15-3.65 (m, 7H), 3.82-3.95 (m, 1H), 4.0-4.1 (m, 2H) (M, 1H), 5.99 (s, 1H, OH), 6.40-6.45 (m, 2H), 6.90-7.0 (m, 3H), 7.25-7.75 35 (m, 2H), 7.64 (m, 1H).

Example 75

(3R) -3 - [(2S) -2-cyclohexyl-2-fur-2-yl-2-hydroxyacetoxy] -1- (3-thien-2-ylpropyl) -1-azonia-bicyclo [ 2.2.2] octane The title compound was synthesized as in Example 74. The yield of the final step was 3.6 mg, 6%. MS [M-CF 3 COO] +: 458. 1 H-NMR (DMSOd 6): δ 1.0-1.45 (m, 7H), 1.50-2.10 (m, 9H), 2.15- 2.30 (m, 2H), 2.75-2.90 (m, 2H), 3.10-3.55 (m, 7H), 3.77-3.92 (m, 1H) 13 (m, 1H), 5.98 (s, 1H, OH), 6.36-6.46 (m, 2H), 6.92-7.02 (m, 2H), 7.36-7, 40 (m, 1H), 7.62 (m, 1H). 127 ΡΕ1353919

Example 76

(3R) -3 - [(2S) -2-Cyclohexyl-2-fur-2-yl-2-hydroxyacetoxy] -1-phenethyl-1-azoniabicyclo [2.2.2] octane trifluoroacetate The title compound was synthesized as in Example 74. The yield of the final step was 2.4 mg, 4.2%. MS [M-CF 3 COO] +: 438. 1 H-NMR (DMSO-d 6): δ 1.0-1.45 (m, 7H), 1.50-2.05 (m, 7H), 2.20 (M, 2H), 3.20-3.65 (m, 7H), 3.85-3.95 (m, 1H), 5.35 (m, (M, 1H), 6.0 (s, 2H, OH), 6.37-6.47 (m, 2H), 7.25-7.45 (m, 5H), 7.64 (m, 1H).

Example 77

(3R) -3 - [(2S) -2-Cyclohexyl-2-fur-2-yl-2-hydroxyacetoxy] -1- (3-phenylpropyl) -1-azonia-bicyclo [2.2.2] octane The title compound was synthesized as in Example 74. The yield of the final step was 2.8 mg, 4.8%. MS [M-CF 3 COO] +: 452. 128 ΡΕ1353919 1 H-NMR (DMSO-d6): δ0.1.1 LO (Ti, 50 (m, 7H), O (m, 9H), 2.15-2.32 (m, 2H), 2.55-2.65 (m, 2H), 3.10-3.60 (m, 7H), 3.77 (M, 1H), 5.98 (s, 1H, OH), 6.36-6.46 (m, 2H), 7.18-7.40 (m, 5H), 7.62 (m, 1H) *

Example 78

(3R) -3 - [(2S) -2-cyclohexyl-2-fur-2-yl-2-hydroxyacetoxy] -1- (3-phenoxypropyl) -1-azonia-bicyclo [2.2.2] octane The title compound was synthesized according to methods c and e from intermediate I-4b. The yield of the final step was 3.0 mg, 5%. MS [M-CF 3 COO] +: 468. 1 H-NMR (DMSO-d 6): δ 1.0-1.45 (m, 7H), 1.55-175 (m, 3H), 1.80-2.05 ( (m, 4H), 2.05-2.25 (m, 3H), 2.30 (m, 1H), 3.10-3.20 (m, 1H), 3.20-3.60 (m, 6H), 3.85-3.95 (m, 1H), 3.95-4.10 (m, 2H), 5.16 (m, 1H), 5.99 (s, 1H, , 40-6.50 (m, 2H), 6.90-7.0 (m, 3H), 7.25-7.38 (m, 2H), 7.64 (m, 1H).

Example 79

(3R) -3 - [(2R) -2-cyclohexyl-2-fur-2-yl-2-hydroxyacetoxy] -1- (3-thien-2-ylpropyl) -1-azonia-bicyclo [ 2.2.2] octane The title compound was synthesized as in Example 78. The yield of the final step was 9.1 mg, 33.1%. MS [M-CF 3 COO] +: 458. 1 H-NMR (DMSO-d 6): δ0.95-1.55 (m, 7H) (M, 2H), 3.0-3.12 (m, 1H), 3.12-3.70 (m, 6H), 1.85 3.80-3.95 (m, 1H), 5.14 (m, 1H), 6.0 (s, 1 H, OH), 6.35-6.55 (m, 2H), 6.90- 7.10 (m, 2H) 7.35-7.45 (m, 1H), 7.60-7.70 (m, 1H).

Example 80

(3R) -3 - [(2R) -2-Cyclohexyl-2-fur-2-yl-2-hydroxyacetoxy] -1-phenethyl-1-azoniabicyclo [2.2.2] octane trifluoroacetate The title compound was synthesized as in Example 78. The yield of the final step was 3.6 mg, 6%. MS [M-CF 3 COO] +: 438.-NMR (DMSO-d 6) δ 1.0- 1.45 (m, 7H), 1.11 (m, 3H). (M, 1H), 2.30 (m, 1H), 2.90-3.0 (m, 1H), 2.30 (m, 2H), 3.15-3.25 (m, 1H), 3.25-0.001 (m, 5H), 3.50-3.95 (m, 1H), 3.85- (M, 1H), 6.0 (s, 1H, OH), 6.38-6.48 (m, 2H), 7.24-7.38 (m, 40 (m, 5H), 7.65 (m, 1H). 130 ΡΕ1353919

Example 81

(3R) -3 - [(2R) -2-cyclohexyl-2-fur-2-yl-2-hydroxyacetoxy] -1- (3-phenylpropyl) -1-azonia-bicyclo [2.2.2] octane The title compound was synthesized as in Example 78. The yield of the final step was 5.8 mg, 10%. MS [M-CF 3 COO] +: 452. 1 H-NMR (DMSO-d 6): δ 1.0-1.42 (m, 7H), 1.55-1.77 (m, 3H), 1.77- 2.05 (m, 6H), 2.18 (m, 1H), 2.27 (m, 1H), 2.55-2.65 (m, 2H), 3.02-3.12 (m, 1H), 3.12-3.60 (m, 6H), 3.77-3.90 (m, 1H), 5.13 (m, 1H), 5.98 (s, 1H, OH), 6 , 40 (m, 2H), 7.20-7.35 (m, 5H), 7.61 (m, 1H).

Example 82

(3R) -3 - [(2R) -2-cyclopentyl-2-hydroxy-2-phenylacetoxy] -1- (3-phenoxypropyl) -1-azoniabicyclo [2.2.2] octane trifluoroacetate The title compound was synthesized according to methods c, and from intermediate I-5a. The yield of the final step was 9.4 mg, 15.6%. MS [M-CF 3 COO] +: 464 131 ΡΕ1353919 ΧΗ-NMR (DMSO-d6): δ 1.10-1.70 (m, 8H), 1.70-2.02 (m, 4H) (M, 2H), 2.24 (m, 1H), 2.90-2.97 (m, 1H), 3.15-3. 25 (m, 1H), 3.25-3.60 (m, 6H), 3.75-3.90 (m, 1H), 3.95-4.10 (m, 2H), 5 , 10 (m, 1H), 5.86 (s, 1H, OH), 6.90-7.0 (m, 3H), 7.20-7.40 (m, 5H), 7.56 -7.66 (m, 2H).

Example 83

(3R) -3 - [(2R) -2-cyclopentyl-2-hydroxy-2-phenylacetoxy] -1-phenethyl-1-azoniabicyclo [2.2.2] octane trifluoroacetate The title compound was synthesized as in Example 82 The yield of the final step was 5.0 mg, 8.8%. MS [M-CF 3 COO]: 434 1 H-NMR (DMSOd 6): δ 1.12-1.70 (m, 8H), 1.75-2.05 (m, 4H), 2.26 (m, (m, 3H), 3.15-3.62 (m, 7H), 3.80-3.92 (m, 1H), 5.13 (m, 1H) , 5.86 (s, 1H, OH) 7.24-7.44 (m, 8H), 7.56-7.66 (m, 2H).

Example 84

(3R) -3 - [(2R) -2-cyclopentyl-2-hydroxy-2-phenylacetoxy] -1- (3'-phenylsulfanylpropyl) -1-azoniabicyclo [2.2.2] octane trifluoroacetate The title compound was synthesized as in Example 82. The yield of the final step was 3.2 mg, 5.1%. MS [M-CF 3 COO] +: 480 1 H-NMR (DMSO-d 6): δ 1.12-1.65 (m, 8H), 1.65-2.0 (m, 6H), 2.21 , 1H), 2.85-3.15 (m, 4H), 3.15-3.55 (m, 6H), 3.70-3.85 (m, 1H), 5.06 (m, 1H ), 5.83 (s, 1H, OH) 7.20-7.46 (m, 8H), 7.54-7.64 (m, 2H).

Example 85

(3R) -3 - [(2S) -2-Cyclopentyl-2-hydroxy-2-phenylacetoxy] -1- (3-phenoxypropyl) -1-azoniabicyclo [2.2.2] octane trifluoroacetate The title compound was synthesized according to methods c and e of intermediate I-5b. The yield of the final step was 7.8 mg, 12.9%. MS [M-CF 3 COO] +: 464-NMR (DMSO-d 6): δ1.35 (m, 2H), 1.35-2.0 (m, 10H), 2.0- 2.30 (m, 3H), 2.95-3.10 (m, 1H), 3.20-3.60 (m, 7H), 3.80-3.95 (m, 1H) (M, 2H), 5.09 (m, 1H), 5.84 (s, 1H, OH), 6.90-7.0 (m, 3H), 7.24 -7.44 (m, 5H), 7.60-7.70 (m, 2H). 133 ΡΕ1353919

Example 86

(3R) -3 - [(2S) -2-Cyclopentyl-2-hydroxy-2-phenylacetoxy] -1-phenethyl-1-azoniabicyclo [2.2.2] octane trifluoroacetate The title compound was synthesized as in Example 85. The yield of the final step was 5.2 mg, 9.2%. MS [M-CF 3 COO] +: 434 1 H-NMR (DMSOd 6): δ1.12-1.32 (m, 2H), 1.32-2.05 (m, 1H), 2.20 (m, m, 1H); 2.90-3.10 (m, 3H), 3.20-3.62 (m, 7H), 3.82-3.97 (m, 1H), 5.12 (m, 1H) 85 (s, 1H, OH), 7.22-7.45 (m, 8H), 7.60-7.70 (m, 2H).

Example 87

(3R) -3 - [(2S) -2-Cyclopentyl-2-hydroxy-2-phenylacetoxy] -1- (3-phenylsulfanylpropyl) -1-azoniabicyclo [2.2.2] octane trifluoroacetate The title compound was synthesized as a white solid as in Example 85. The yield of the final step was 4.0 mg, 6.4%. MS [M-CF 3 COO] +: 480 134 ΡΕ1353919 1 H-NMR (DMSO-d6): δ 1.12-1.32 (m, 2H), 1.32-1.70 (m, 8H), 1.70 -2.0 (m, 4H), 2.16 (m, 1H), 2.92-3.05 (m, 3H), 3.15-3.60 (m, 7H), 3.75-3 (M, 1H), 5.82 (s, 1H, OH), 7.20-7.44 (m, 8H), 7.58-7.68 (m, , 2H).

Example 88

(3R) -3 - [(2S) -2-cyclohexyl-2-hydroxy-2-thien-2-ylacetoxy] -1- (3-phenoxypropyl) -1-azonia-bicyclo [2.2.2] octane The title compound was synthesized according to methods c, and from intermediate I-6a. The yield of the final step was 3.2 mg, 5.1%. MS [M-CF 3 COO] +: 484 1 H-NMR (DMSO-d 6): δ 1.85 (m, 7H) , 1.80-2.20 (m, 7H), 2.25-2.35 (m, 1H), 3.20-3.38 (m, 1H), 3.28-3.42 (m , 5H), 3.42-3.55 (m, 1H), 3.85-3.95 (m, 1H), 4.01-4.05 (m, 2H), 5.17 (m, 1H), 6.16 (s, 1H, OH), 6.92-7.03 (m, 4H), 7.13-7.15 (m, 1H), 7.28-7.34 (m, 2H), 7.42-7.45 (m, 1H).

Example 89

(3R) -3 - [(2S) -2-Cyclohexyl-2-hydroxy-2-thien-2-ylacetoxy] -1-phenethyl-1-azoniabicyclo [2.2.2] octane trifluoroacetate 135 ΡΕ1353919 The compound of the title was synthesized as in Example 88. The yield of the final step was 3.4 mg, 5.8%. MS [M-CF 3 COO] +: 454 1 H-NMR (DMSO-d 6): δ 1.0-1.45 (m, 7H); 1.55-1.80 (m, 3H), 1.80-2 (M, 5H), 2.32 (m, 1H), 2.95-3.05 (m, 2H), 3.20-3.52 (m, 6H), 3.52-3 , 6.68 (m, 1H), 3.85-3.95 (m, 1H), 5.20 (m, 1H), 6.16 (s, 1H, OH), 7.0-7.7 04 (m, 1H), 7.10-7.15 (m, 1H), 7.25-4.40 (m, 5H), 7.34-7.46 (m, 1H).

Example 90

1- [3- (3-Cyanophenoxy) propyl] - (3R) -3 - [(2S) -2-cyclohexyl-2-hydroxy-2-thien-2-ylacetoxy] -1-azoniabicyclo [2.2 2] octane The title compound was synthesized as in Example 88. The yield of the final step was 8.4 mg, 12.7%. MS [M-CF 3 COO] +: 509 1H-NMR (DMSO-d6): δ 1.0-1.45 (m, 7H), 1.55-1.70 (m, 3H), 1.70-2 , 20 (m, 7H), 2.31 (m, 1H), 3.20-3.27 (m, 1H), 3.25-3.50 (m, 5H), 3.45-3.60 (m, 1H), 3.85-3.95 (m, 1H), 4.05-4.15 (m, 2H), 5.18 (m, 1H), 6.16 (s, 1H, OH ), 136 Î'1353919 7.0-7.03 (m, 1H), 7.13-7.15 (m, 1H), 7.28-7.31 (m, 1H), 7.43-7.46 (m, 3H), 7.50-7.55 (m, 1H).

Example 91

(3R) -3 - [(2R) -2-cyclohexyl-2-hydroxy-2-thien-2-ylacetoxy] -1- (3-phenoxypropyl) -1-azonia-bicyclo [2.2.2] octane The title compound was synthesized according to methods c, and from intermediate I-6b. The yield of the final step was 3.0 mg, 4.8%. MS [M-CF 3 COO] +: 484 1 H-NMR (DMSOd 6): δ 1.0-1.50 (m, 7H), 1.55-1.22 (m, 10H), 2.25-2 (M, 1H), 3.45-3.45 (m, 5H), 3.45-3.60 (m, 1H), 3.85-3.95 (m, 1H), 4.0 -4.10 (m, 2H), 5.17 (m, 1H), 6.14 (and 6.16) (S, 1H, OH, mixture of diastereomers ca. 75:25), 6.93-7 , Î'(m, 4H), 7.13-7.17 (m, 1H), 7.28-7.35 (m, 2H), 7.42-7.45 (m, 1H).

Example 92

(3R) -3 - [(2R) -2-cyclohexyl-2-hydroxy-2-thien-2-ylacetoxy] -1-phenethyl-1-azoniabicyclo [2.2.2] octane trifluoroacetate The title compound was synthesized as in 137 ΡΕ1353919

Example 91. The yield of the final step was 2.6 mg, 4.4%. MS [M-CF 3 COO] +: 454 1H-NMR (DMSO-d6): δ 1.50-1.70 (m, 7H), 1.55-2.20 (m, 8H), 2.28 (M, 1H), 2.95-3.10 (m, 2H), 3.20-3.52 (m, 6H), 3.52-3.65 (m, 1H), 3.85-3.97 m), 5.15-5.25 (m, 1H), 6.14 (s, 1H, OH, diastereomer mixture approx: 75:25), 6,98- 7.04 (m, 1H), 7.13-7.16 (m, 1H), 7.25-7.40 (m, 5H), 7.34-7.46 (m, 1H).

Example 93

1- [3- (3-Cyanophenoxy) propyl] - (3R) -3 - [(2R) -2-cyclohexyl-2-hydroxy-2-thien-2-ylacetoxy] -1-azoniabicyclo [2.2 2] octane The title compound was synthesized as in Example 91. The yield of the final step was 5.0 mg, 7.5%. MS [M-CF 3 COO] +: 509 1 H-NMR (DMSOd 6): δ 1.0-1.50 (m, 7H), 1.55-2.05 (m, 7H), 2.05-2 , 22 (m, 3H), 2.22-2.35 (m, 1H), 3.20-3.50 (m, 6H), 3.45-3.60 (m, (M, 2H), 5.17 (m, 1H), 6.14 (s, 6.16) (s, 1H, OH, mixture of diastereomers ca. 75:25), 7.0-7.03 (m, 1H), 7.13-7.16 (m, 1H), 7.38-7.32 (m, 1H) , 7.43-7.46 (m, 3H), 7.50-7.55 (m, 1H).

Example 94

(3R) -3- (2-Hydroxy-4-phenyl-2-thien-2-ylbutanoyloxy) -1- (3-phenoxypropyl) -1-azoniabicyclo [2.2.2] octane trifluoroacetate The title compound was synthesized as a mixture of diastereomers according to the methods d, and from intermediate 1-21. The yield of the final step was 4.8 mg, 15.8%. MS [M-CF 3 COO] +: 50 (5 R-NMR (DMSO-d, δ): δ 1.75-2.05 (m, 3H), 2.05-2.20 (m, 2H), 2. , 2.20-2.35 (m, 2H), 2.20-2.35 (m, 2H), 2.37-2.70 (m, 4H), 3.20-3.65 (m, 7H ), 3.82-3.95 (m, 1H), 4.0-4.1 (m, 2H), 5.12 (m, 1H), 6.58 (s, 1H, (M, 4H), 7.24-7.24 (m, 4H), 7.25-7.36 (m, 4H) , 7.46-7.52 (m, 1H).

Example 95

(3S) -3 - [(2S) -2-Cyclopentyl-2-hydroxy-2-thien-2-ylacetoxy] -1- (3-phenoxypropyl) -1-azoniabicyclo [2.2.2] octane bromide 139 ΡΕ1353919 The title compound was synthesized according to methods c, and from intermediate 1-7. The yield of the final step was 250 mg, 87.1%. MS [M-Br] +: 470 1 H-NMR (DMSO-d 6): δ (the same description as in

Example 53).

Example 96

(3S) -3 - [(2S) -2-Cyclopentyl-2-hydroxy-2-thien-2-ylacetoxy] -1- (3-thien-2-ylpropyl) -1-azoniabicyclo [2.2.2] octane

The title compound was synthesized according to methods c, and a from intermediate 1-7. The yield of the final step was 11.1 mg, 40.2%. MS [M-CF 3 COO] +: 460 1 H-NMR (DMSO-d 6): δ (same description as in

Example 54).

Example 97

(3S) -3 - [(2S) -2-Cyclopentyl-2-hydroxy-2-thien-2-ylacetoxy] -1- (3-phenylpropyl) -1-azonia-bicyclo [2.2.2] octane trifluoroacetate ΡΕ1353919 The title compound was synthesized as in Example 96. The yield of the final step was 11.3 mg, 41.4%. MS [M-CF 3 COO] +: 454 1 H-NMR (DMSO-d 6): δ (same description as Example 57).

Example 98

4 - [(2R) -2-Cyclohexyl-2-hydroxy-2-phenylacetoxy] -1- (3-thien-2-ylpropyl) -1-azoniabicyclo [2.2.2] octane trifluoroacetate The title compound was synthesized according to methods c and e from intermediate 1-8. The yield of the final step was 9.4 mg, 34.6%. MS [M-CF 3 COO] +: 468 1H-NMR (DMSO-d6): δ 0.90-1.65 (m, 9H), 1.70-1.80 (m, 1H), 1.90-2 (M, 2H), 2.05-2.20 (m, 1H), 2.18-2.35 (m, 6H), 2.75-2.90 (m, 2H), 3.10 3.25 (m, 2H), 3.45-3.70 (m, 6H), 5.60 (s, 1H, OH), 6.90-6.92 (m, 1H), 6.95 -7.02 (m, 1H), 7.20-7.45 (m, 4H), 7.50-7.60 (m, 2H). 141 ΡΕ1353919

Example 99

4 - [(2S) -2-Cyclohexyl-2-hydroxy-2-phenylacetoxy] -1- (3-phenoxypropyl) -1-azoniabicyclo [2.2.2] octane trifluoroacetate The title compound was synthesized as in Example 98. The yield of the final step was 8.1 mg, 29.2%. MS [M-CF 3 COO] +: 478 1 H-NMR (DMSO-d 6): δ 0.90-1.65 (m, 9H), 1.70-1.80 (m, 1H), 2.05-2 , 20 (m, 3H), 2.20-2.40 (m, 6H), 3.20-3.45 (m, 2H), 3.50-3.75 (m, 6H), 3.95 -4.10 (m, 2H), 5.60 (s, 1H, OH), 6.85-7.05 (m, 3H), 7.20-7.45 (m, 5H), 7.50 -7.65 (m, 2H). ((*): Configuration not determined)

The following examples illustrate pharmaceutical compositions according to the present invention and procedures for their preparation.

Example 100

Preparation of a pharmaceutical composition: tablets ΡΕ1353919 142

Formulation:

Compound of the present invention 5.0 mg Lactose 113.6 mg Microcrystalline cellulose 28.4 mg Light silicic anhydride 1.5 mg Magnesium stearate 1.5 mg

Using a blender, 15 g of the compound of the present invention was mixed with 340.8 g of lactose and 85.2 g of microcrystalline cellulose. The blend was subjected to compression molding using a roller compactor to give a flake type compressed material. The flake-type compressed material was pulverized using a hammer mill and the pulverized material was sifted through a 20 mesh screen. A 4.5 g portion of light silicic anhydride and 4.5 g of magnesium stearate was added to the sieved material and mixed. The mixer product was compressed into a tabletting machine with a 7.5 mm diameter die / matrix system, thereby obtaining 3000 tablets, each having 150 mg of weight.

Example 101

Preparation of a pharmaceutical composition: coated tablets ΡΕ1353919 143

Formulation:

Compound of the present invention 5.0 mg

Lactose 95.2 mg

Corn starch 40.8 mg

Polyvinylpyrrolidone K25 7.5 mg

Magnesium stearate 1.5 mg

Hydroxypropylcellulose 2.3 g

Polyethylene glycol 6000 0.4 mg

Titanium dioxide 1.1 mg

Purified talc 0.7 mg

Using a fluidized bed granulation apparatus, 15 g of the compound of the present invention was mixed with 285.6 g of lactose and 122.4 g of starch. Separately, 22.5 g of polyvinylpyrrolidone was dissolved in 127.5 g of water to prepare a binder solution. Using a fluidized bed granulation apparatus, the binder solution was sprayed onto the above mixture to give granules. A 4.5 g portion of magnesium stearate was added to the obtained granules and mixed. The obtained blend was compressed into a tabletting apparatus with a 6.5 mm diameter biconvex die / punch system, thereby obtaining 3000 tablets, each having 150 mg of weight. 144 ΡΕ1353919

Separately, a coating solution was prepared by suspending 6.9 g of hydroxypropyl methylcellulose 2910, 1.2 g of polyethylene glycol 6000, 3.3 g of titanium dioxide and 2.1 g of purified talc in 72.6 g of water. Using a High Coated, the 3000 tablets prepared above were coated with the coating solution to give film-coated tablets, each being 154.5 mg in weight.

Example 102

Preparation of a pharmaceutical composition: inhalation liquid

Formulation:

Compound of the present invention 400 pg

Physiological saline solution 1 ml

A 40 mg portion of the compounds of the present invention was dissolved in 90 ml of physiological saline, and the solution was adjusted to a total volume of 100 ml with the same saline solution, dispensed in 1 ml portions in an ampoule with a capacity of 1 ml and then sterilized at 115 ° C for 30 minutes to give a liquid for inhalation. 145 ΡΕ1353919

Example 103

Preparation of a pharmaceutical composition: inhalation powder

Formulation:

Compound of the invention 200 pg

Lactose 4000 pg

A 20 g portion of the compound of the present invention was uniformly mixed with 400 g of lactose, and a 200 mg portion of the blend was packed in a powder inhaler for use solely to produce an inhalation powder.

Example 104

Preparation of a pharmaceutical composition: inhalation aerosol

Formulation:

Compound of the present invention 200 pg Dehydrated ethyl alcohol (absolute) USP 8400 pg 1,1,1,2-tetrafluoroethane (HFC-134A) 46810 pg The active ingredient concentrate is prepared by dissolving 0.0480 g of the compound of the present invention in 2.0160 g of ethyl alcohol. The concentrate is added 146 ΡΕ1353919 to a suitable filler. The active ingredient concentrate is dispensed into an aerosol container, the container cleared by being purged with HFC-134A nitrogen or vapor (the purge ingredients should not contain more than 1 ppm oxygen) and is sealed with a valve. 11.2344 g of the HFC-134A propellant is then filled under pressure in the sealed vessel.

Lisbon, September 29, 2006

Claims (34)

A compound of formula (I) m H4 RT RS X " wherein B is a phenyl ring, a 5- to 10-membered heteroaromatic group containing one or more heteroatoms selected from N, O, O, or a naphthalenyl, 5,6,7,8-tetrahydronaphthalenyl, benzo [1,3] dioxolyl, or a biphenyl group; R 1, R 2 and R 3 each independently represents a hydrogen or halogen atom, or a phenyl group, a -OR 7, -SR 7, -NR 7 R 8, -NHCOR 7, -CONR 7 R 8, -CN, -NO 2, -COR 7 or CF 3 group, or a linear or branched C1 to C6 alkyl group which is unsubstituted or substituted with one or more halogen atoms, hydroxyl groups or C1 to C6 alkoxy groups, wherein R7 and R8 each independently represent a hydrogen atom, a straight chain or branched C1 to C6 alkyl, or together form a C3 to C6 alicyclic ring; or R1 and R2 together form a C5 to C14 or C3 to C6 alicyclic aromatic ring or a 5- to 10-membered heterocyclic 2 Ρ P1353919 group containing one or more heteroatoms selected from N, S and O; n is an integer from 0 to 4; A represents a group selected from -CH = CHR9-, -CR9 = CH-, -CR9R10-, -CO-, -O-, -S-, -S (O) -, -S (O) 2- and NR9 , wherein R9 and R10 each independently represent a hydrogen atom, a linear or branched C1 to C8 alkyl group, or together form a C3 to C8 alicyclic ring; m is an integer from 0 to 8, provided that when m = 0, A is not -CH 2 -; p is an integer from 1 to 2 and the substitution on the bicyclic azonia ring may be in the 2, 3 or 4 position including all possible configurations of the asymmetric carbons; R 4 represents a group of structure: wherein R11 represents a hydrogen or halogen atom, a hydroxyl group, a C1 to C6 alkoxy group, a nitro group, a cyano group, -C02 R12 or -NR12 R13 in which R12 is an identical or different and are selected hydrogen and straight chain or branched C1 to C6 alkyl groups, or a linear or branched C1 to C6 alkyl group which is unsubstituted or substituted with one or more halogen atoms, hydroxyl groups or C1 to C6 alkoxy groups; R 5 represents an alkyl group of 1 to 7 carbon atoms, an alkenyl group containing 2 to 7 carbon atoms, an alkynyl group containing 2 to 7 carbon atoms, a cycloalkyl group of 3 to 7 carbon atoms, or a group of formula R11 wherein q = 1 or 2 and R11 is as defined above; R 6 represents a hydrogen atom, a hydroxide group, a methyl group or a -CH 2 OH group; and X represents a pharmaceutically acceptable anion of a mono or polyvalent acid. A compound according to claim 1, wherein p is 2. 4 ΡΕ 1355919 A compound according to claim 1 or 2, wherein R 4 represents an unsubstituted phenyl, 2-thienyl, 3-thienyl, 2-furyl or 3-furyl group. A compound according to any one of the preceding claims, wherein R 5 represents a cyclopentyl, cyclohexyl, pentyl, allyl, vinyl, propynyl, benzyl or phenethyl group. A compound according to any one of the preceding claims, wherein the group -O-CO-C (R 4) (R 5) (R 1) represents a group selected from 2-cyclopentyl-2-hydroxy- 2-ylacetoxy, 2,3-diphenylpropionyloxy; 2-hydroxymethyl-2,3-diphenylpropionyloxy; 2-hydroxy-2,3-diphenylpropionyloxy; 2-hydroxy-3-phenyl-2-thien-2-ylpropionyloxy; 2-hydroxy-2-thien-2-ylpent-4-enoyloxy; 2-hydroxy-2-thien-2-yl-heptanoyloxy; 2-hydroxy-2-thien-2-ylpent-3-ynoyloxy; 2-hydroxy-2-thien-2-ylbut-3-enoyloxy; 2-cyclopentyl-2-fur-2-yl-2-hydroxyacetoxy; 2-cyclohexyl-2-hydroxy-2-phenylacetoxy; 2-cyclohexyl-2-fur-2-yl-2-hydroxyacetoxy; 2-cyclopentyl-2-hydroxy-2-phenylacetoxy; 2-cyclohexyl-2-hydroxy-2-thien-2-ylacetoxy and 2-hydroxy-4-phenyl-2-thien-2-ylbutenoyloxy. A compound according to any one of the preceding claims, wherein B represents a phenyl, pyrrolyl, thienyl, furyl, biphenyl, naphthalenyl, 5,6,7,8-tetrahydronaphthalenyl, benzo [1,3] dioxolyl, imidi -Zazolyl, or benzothiazolyl. 5 ΡΕ1353919 A compound according to claim 6, wherein B represents a phenyl, pyrrolyl or thienyl group. A compound according to any one of the preceding claims, wherein R 1, R 2 and R 3 each independently represents a hydrogen or halogen atom or a hydroxyl, methyl, tert-butyl, -CH 2 OH, 3-hydroxypropyl, -OMe, -NMe 2, -NHCOMe, -CONH 2, -CN, -NO 2, -COOMe or -CF 3. A compound according to claim 8, wherein R 1, R 2 and R 3 are each independently a hydrogen, halogen or hydroxyl group. A compound according to any one of the preceding claims, wherein n = 0 or 1; m is an integer from 1 to 6; and A represents a group -CH 2 -, -CH = CH-, -CO-, -NMe-, -O- or -S-. A compound according to claim 10, wherein m is 1, 2 or 3 and A represents -CH 2 -, -CH = CH-, -O- or -S-. A compound according to any one of the preceding claims, wherein the azoniabicyclo group is substituted on the nitrogen atom with a 3-phenoxypropyl, 2-phenoxyethyl, 3-phenylallyl, phenethyl, 3-phenylpropyl, 3- (3-hydroxyphenoxy ) propyl, 3- (4-fluorophenoxy) propyl, 3-6 Ρ E1353919 thien-2-ylpropyl, 4-oxo-4-thien-2-ylbutyl, 2-benzoyloxyethyl, 3- (3-cyanophenoxy) propyl, 3- - (methylphenylaminio) propyl, 3-phenylsulfanylpropyl, 4-oxo-4-phenylbutyl, 3- (2-chlorophenoxy) propyl, 3- (2,4-difluorophenoxy) propyl, 3- (4-methoxyphenoxy) propyl, 3- benzo [1,3] dioxol-5-yloxy) propyl A compound according to any one of the preceding claims, wherein X represents a chloride, bromide, trifluoroacetate or methanesulfonate anion. A compound according to any one of the preceding claims, wherein the azoniabicyclo group is substituted in the 3-position. A compound according to claim 14, wherein the 3-position substituent of the azoniabicyclo group has a R configuration. A compound according to claim 14, wherein the 3-position substituent of the azoniabicyclo group has the S configuration. A compound according to any one of the preceding claims, wherein the carbon substituted with R 4, R 5 and R 6 has the R configuration. A compound according to any one of claims 1 to 16, wherein the carbon substituted with R 4, R 5 and R 6 has the configuration S. 7 ΡΕ 1355919 A compound according to any one of the preceding claims, which is a single isomer. A compound according to claim 1 which is: (3R) -3- (2,3-diphenylpropionyloxy) -1- (3-phenoxypropyl) -1-azoniabicyclo [2.2.2] octane trifluoroacetate 3R) -3- (2,3-diphenylpropionyloxy) -1- (3-thien-2-ylpropyl) -1-azoniabicyclo [2.2.2] octane (3R) -3- (2-hydroxymethyl-2- , 3-diphenylpropionyloxy) -1- (3-thien-2-ylpropyl) -1-azoniabicyclo [2.2.2] octane (3R) -3- (2-hydroxymethyl-2,3-diphenylpropionyloxy] -1- phenethyl-1-azoniabicyclo [2.2.2] octane (3R) -3- (2-hydroxymethyl-2,3-diphenyl-propionyloxy) -1- (3-phenoxypropyl) -1-azoniabicyclo [2.2.2] octane bromide (3R) -3- (2-hydroxy-2,3-diphenylpropionyloxy] -1- (2-phenoxyethyl) -1-azoniabicyclo [2.2.2] octane bromide 2-hydroxymethyl-2,3-difen-nylpropionyloxy] -1- (2-phenoxypropyl) -1-azoniabicyclo [2.2.2] octane (diastereomer 1) (3R) -3- (2- hydroxy-3-phenyl-2-thien-2-ylpropionyloxy] -1- (3-phenoxypropyl) -1-azoniabicyclo [2.2.2] octane (3R) -3- 2-ylpropyl) -1-azonia-bicyclo [2.2.2] octane hydrochloride δΕ1353919 (3R) -3- (2-Amino- hydroxy-2-thien-2-ylpentenoyloxy] -1- (3-phenoxypropyl) -1-azoniabicyclo [2.2.2] octane Trifluoroacetate (3R) -3- (2-hydroxy-2-thien-1-ylpent-4 (3R) -3- (2-hydroxy-2-thien-2-yl) pentenoyloxy] -1- (3-thien-2-ylpropyl) -1-azoniabicyclo [2.2.2] (3R) -3- (2-hydroxy-2-thien-1-yl-heptanoyloxy) -1- (3-phenoxypropyl) -1-azoniabicyclo [2.2.2] octane trifluoroacetate 2.2.2 octane (3R) -3- (2-hydroxy-2-thien-1-yl-heptanoyloxy) -1- (3-thien-2-ylpropyl) -1-azoniabicyclo [2.2.2] octane trifluoroacetate (3R) -3- (2-hydroxy-2-thienylpent-3-yloxy] -1- (3-phenoxypropyl) -1-azoniabicyclo [2.2.2] octane trifluoroacetate 3-yloxy) -1- (3-thien-2-ylpropyl) -1-azoniabicyclo [2.2.2] octane (3R) -3- (2-Hydroxy-2 3-yloxy) -1- (3-phenoxypropyl) -1-azoniabicycl (3R) -3- (2-hydroxy-2-thien-1-yl-butyloxy) -1- (3-thien-2-ylpropyl) -1-azoniabicyclo [2.2.2] octane Trifluoroacetate (2S) -2-cyclopentyl-2-hydroxy-2-thien-2-ylacetoxy] -1- (3-phenoxypropyl) -1-azoniabicyclo [2.2.2] octane 9 ΡΕ1353919 (3R) -3 - [(2S) -2-Cyclopentyl-hydroxy-2-thien-2-ylacetoxy] -1- (3-thien-2-ylpropyl) -1-azonia bicyclo [2.2.1] (2S) -2-cyclopentyl-2-hydroxy-2-thien-2-ylacetoxy] -1- (2-phenoxyethyl) -1-azoniabicyclo [2.2.2] octane bromide (3R) -3-Cyclopentyloxy-2-thien-2-ylacetoxy] -1-phenethyl-1-azoniabicyclo [2.2.2] octane Trifluoroacetate (3R) -3 - [(2S) -2- [(2S) -2-Cyclopentylhydroxy-2-thien-2-ylacetoxy] -1- (3-phenylpropyl) -1-azonia-bicyclo [2.2.2] octane (3R) -3 - [(2S ) -2-cyclopentylhydroxy-2-thien-2-ylacetoxy] -1- (3-phenylalan) -1-azonia-bicyclo [2.2.2] octane (3R) -3 - [(2S) -2- -cyclopentyl-hydroxy-2-thien-2-ylacetoxy] -1- [3- (4-fluorophenoxy) propyl] -α (4-oxo-4-thien-2-ylbutyl) -2-cyclopentylhydroxy-2-thien-2-ylacetoxy] -1- (4-oxo- (3R) -3 - [(2S) -2-cyclopentylhydroxy-2-thien-2-ylacetoxy] -1- [4- (4-fluorophenyl) -4-azoniabicyclo [2.2.2] octane Trifluoroacetate (3R) -3 - [(2S) -2-cyclopentylhydroxy-2-thien-2-ylacetoxy] -1- [3- (3-oxo-butyl] -1-azoniabicyclo [2.2.2] 1- (2-benzyloxyethyl) - (3R) - [(2S) -2-cyclopentyl-2-hydroxy-2-thien-2-ylacetoxy] -piperidine-1-azoniabicyclo [2.2.2] octane trifluoroacetate (3R) -3 - [(2S) -2-cyclopentyl-2-hydroxy-2-thien-2-ylacetoxy] -1- (3-o-tolyloxypropyl) -1-azoniabicyclo [2.2.2] octane 1- [3- (3-Cyanophenoxy) propyl] - (3R) -3 - [(2S) -2-cyclopentyl-2-hydroxy- (3R) -3 - [(2S) -2-cyclopentyl-2-hydroxy-2-thien-2-ylacetoxy] -1- [3- (naphthalen- 1-yloxy) propyl] -1-azoniabicyclo [2.2.2] octane Trifluoroacetate of (3R) -3 - [(2S) -2-cyclopentyl-2-hydroxy-2-thien-2-ylacetoxy] -1- [3- (methylphenylamino) propyl] -1-azoniabicyclo [2.2.2] octane Trifluoroacetate of (3R) -3 - [(2S) -2-cyclopentyl-2-hydroxy-2-thien-2-ylacetoxy] -1- (3-phenylsulfanylpropyl) -1-azoniabicyclo [2.2.2] octane trifluoroacetate ) -3 - [(2S) -2-cyclopentyl-2-hydroxy-2-thien-2-ylacetoxy] -1- (4-oxo-4-phenylbutyl) -1-azoniabicyclo [2.2.2] octane trifluoroacetate 3R) -3 - [(2S) -2-cyclopentyl-2-hydroxy-2-thien-2-ylacetoxy] -1- [3- (2,4,6-trimethylphenoxy) propyl] -1-azoniabicyclo [2.2 1- [3- (2-chlorophenoxy) propyl] - (3R) -3 - [(2S) -2-cyclopentyl-2-hydroxy-2-thien-2-ylacetoxy] -1-azoniabicyclo [ (3R) -3 - [(2S) -2-cyclopentyl-2-hydroxy-2-thien-2-ylacetoxy] -1- [3- (3-trifluoromethylphenenoxy) propyl] 1- [3- (biphenyl-4-yloxy) propyl] - (3R) -3 - [(2S) -2-cyclopentyl-2-hydroxy-2-thien- 2-ylacetoxy] -1-azoniabicyclo [2.2.2] octane trifluoroacetate 11β3133919 (3R) -3 - [(2S) -2-cyclopentyl-2-hydroxy-2-thien-2-ylacetoxy] -1- [3- (2,4-difluorophenoxy) pro-pyl] -1-azoniabicyclo [2.2.2] octane (3R) - 3 - [(2S) -2-cyclopentyl-2-hydroxy-2-thien-2-ylacetoxy] -1- [3- (4-methoxyphenoxy) propyl] -1-azoniabicyclo [2.2.2] octane trifluoroacetate ) -3 - [(2S) -2-cyclopentyl-2-hydroxy-2-thien-2-ylacetoxy] -1- [3- (5,6,7,8-tetrahydro-naphthalen-2-yloxy) propyl] -1-azoniabicyclo [2.2.2] octane 1- [3- (Benzo [1,3] dioxol-5-yloxy) propyl] - (3R) -3 - [(2S) -2-cyclopentyl] 1- [3- (2-carbamoylphenoxy) propyl] - (3R) -3 - [(2S) -2-hydroxy-2-thien-2-ylacetoxy] -1-azoniabicyclo [2.2.2] octane trifluoroacetate (3R) -3 - [(2S) -2-cyclopentyl-2-hydroxy-2-thien-2-yl] -acetoxy] -1-azoniabicyclo [2.2.2] 2-ylacetoxy] - [3- (3-dimethylaminophenoxy) pro-pyl] -1-azoniabicyclo [2.2.2] octane 1- [3- (4-Acetylaminophenoxy) propyl] - (3R) -3- [ (2S) -2-cyclopentyl-2-hydroxy-2-thien-2-ylacetoxy] -1-azoniabicyclo [2.2.2] octane R) -3 - [(2S) -2-cyclopentyl-2-hydroxy-2-thien-2-ylacetoxy] -1- [3- (4-methoxycarbonylphenenoxy) propyl] -1-azoniabicyclo [2.2.2] octane Trifluoroacetate (3R) -3 - [(2S) -2-cyclopentyl-2-hydroxy-2-thien-2-ylacetoxy] -1- [3- (4-nitrophenoxy) propyl] -1-azoniabicyclo [2.2.1] 3-yl) -2-cyclopentyl-2-hydroxy-2-thien-2-ylacetoxy] -1- [3- (4-hydroxymethylphenoxy) propyl] -1- (3R) -3 - [(2R) -2-Cyclopentyl-2-hydroxy-2-thien-2-ylacetoxy] -1- [3- (3-phenoxypropyl) -1-azoniabicyclo [2.2.2] -azoniabicyclo [2.2.2] octane Hydroxy-2-thien-2-ylacetoxy] -1-bicyclo [2.2.2] octane Trifluoroacetate Hydroxy-2-thien-2-ylacetoxy] -1-cyclo [2.2.2] hydroxy-2-thiazol-2-ylacetoxy] -1 [2.2.2] octane Trihydroxy-2-thienohydro-2-thien-2-ylacetoxy] -1- [2,2,2] octane trifluoroacetate -2-ylacetoxy] -1-cyclo [2.2.2] octane Hydroxy-2-thien-2-ylacetoxy] -1-azoniabicyclo [2.2.2] octane trifluoroacetate Fur-2-yl-2-hydroxy trifluoroacetate oxyacetoxy] -1-cyclo [2.2.2] octane Fur-2-yl-2-hydroxyacetoxy] -1-bicyclo [2.2.2] octane Trifluoroacetate (3R) -3 - [(2R) -2- (3R) -3 - [(2R) -2-cyclopentyl-2- (2-phenoxyethyl) -1-azoniabicyclo- (3R) -3- 1-azoniabicyclo (3 R) -3 - [(2 R) -2-cyclopentyl-2- (3-phenylpropyl) (3R) -3 - [(2R) -2-cyclopentyl-2- [3- (4-fluorophenoxy) propyl] -1- (2R) -2-cyclopentyl-2- (3-phenyl) - (3R) -3 - [(2S) -2-cyclopentyl-2-3-phenoxypropyl) -1-azoniabi- (3R) -3 - [(2S) -2-cyclopentyl-2-3-thien-2 1-azonia- (3R) -3 - [(2S) -2-cyclopentyl-2-fur-2-yl-2-hydroxyacetoxy] -1-phenethyl-1-azoniabicyclo [2.2.2] octane (3R) -3 - [(2S) -2-cyclopentyl-fur-2-yl-2-hydroxyacetoxy] -1- (3-phenylpropyl) -1-azoniabicyclo [2.2.2] octane trifluoroacetate (3R) -3 - [(2R) -2-cyclopentyl-fur-2-yl-2-hydroxyacetoxy] -1- (3-phenoxypropyl) -1-azoniabic acid [2.2.2] octane trifluoroacetate 3 - [(2R) -2-cyclic (3R) -3 - [(2R) -2-Aminoethyl] -2-hydroxyethyl] -1- (3-thien-2-ylpropyl) -1-azonia bicyclo [2.2.2] octane Trifluoroacetate (3R) -3 - [(2R) -2-Cyclopentyl-fur-2-yl] -2-cyclopentyl-fur-2-yl-2-hydroxyacetoxy] -1-phenethyl-1-azoniabicyclo [2.2.2] 2-hydroxyacetoxy] -1- (3-phenylpropyl) -1-azoniabicyclo [2.2.2] octane Trifluoroacetate (3R) -3 - [(2R) -2-cyclohexylhydroxy-2-phenylacetoxy] -1- (3R) -3 - [(2R) -2-cyclohexyl-hydroxy-2-phenylacetoxy] -1- (3-thienyl) -1- (3-phenoxypropyl) -1-azoniabicyclo [2.2.2] (3R) -3 - [(2R) -2-cyclohexylhydroxy-2-phenylacetoxy] -1-phenethyl-1-azoniabicyclo [2.2.2] octane trifluoroacetate (3R) -3 - [(2S) -2-cyclohexylhydroxy-2-phenylacetoxy] -1- (3-phenoxypropyl) -1-azoniabicyclo [2.2.2] octane trifluoroacetate octane Trifluoroacetate (3R) -3 - [(2S) -2-cyclohexylhydroxy-2-phenylacetoxy] -1- (3-thien-2-ylpropyl) -1-azonia-bicyclo [2.2.2] octane trifluoroacetate 14 ΡΕ1353919 (3R) -3 - [(2S) -2-Cyclohexylhyd trifluoroacetate (3R) -3 - [(2S) -2-cyclohexyl-fur-2-yl-2-hydroxyacetoxy] -2-phenylacetoxy] -1-phenethyl-1-azoniabicyclo [2.2.2] octane trifluoroacetate (3R) -3 - [(2S) -2-Cyclohexyl-fur-2-yl-2-hydroxyacetoxy] -1- (3-phenoxypropyl) -1-azonia-bicyclo [2.2.2] octane trifluoroacetate (3R) -3 - [(2S) -2-Cyclohexyl-fur-2-yl-2-hydroxyacetoxy] -1- (3-thien-2-ylpropyl) -1-azonia bicyclo [2.2.2] ] - 1 - (3S) -2-Cyclohexyl-fur-2-yl-2-hydroxyacetoxy] -1- (3 (3R) -3 - [(2R) -2-cyclohexyl-fur-2-yl-2-hydroxyacetoxy] -1- (3-phenoxypropyl) -1-azoniabicyclo [2.2.2] octane trifluoroacetate ) -1-azonia-bicyclo [2.2.2] octane (3R) -3 - [(2R) -2-cyclohexyl-fur-2-yl-2-hydroxyacetoxy] -1- (3-thien- (3R) -3 - [(2R) -2-cyclohexyl-fur-2-yl-2-hydroxyacetoxy] -1-phenethyl-1-azabicyclo [2.2.2] octane trifluoroacetate (3R) -3 - [(2R) -2-cyclohexyl-fur-2-yl-2-hydroxyacetoxyl trifluoroacetate (3R) -3 - [(2R) -2-cyclopentylhydroxy-2-phenylacetoxy] -1- (3-phenylpropyl) -1-azoniabicyclo [2.2.2] octane Trifluoroacetate (3R) -3 - [(2R) -2-cyclopentyl-2-hydroxy-2-phenylacetoxy] -1-phenethyl-1-azoniabicyclo [3.2.2] octane trifluoroacetate (3R) -3 - [(2R) -2-cyclopentyl-2-hydroxy-2-phenylacetoxy] -1- (3-phenylsulfanylpropyl) -1-azonia-bicyclo [2.2.2] octane Trifluoroacetate ] octane Trifluoroacetate (3R) -3 - [(2S) -2-cyclopentyl-2-hydroxy-2-phenylacetoxy] -1- (3-phenoxypropyl) -1-azoniabicyclo [2.2.2] octane Trifluoroacetate ) -3 - [(2S) -2-Cyclopentyl-2-hydroxy-2-phenylacetoxy] -1-phenethyl-1-azoniabicyclo [2.2.2] octane Trifluoroacetate (3R) -3 - [(2S) -2-cyclohexyl-2-phenylacetoxy] -1- (3-phenylsulfanylpropyl) -1-azonia-bicyclo [2.2.2] octane Trifluoroacetate 2-hydroxy-2-thien-2-ylacetoxy] -1- (3-phenoxypropyl) -1-azonia-bicyclo [2.2.2] octane (3R) -3 - [(2S) -2-cyclohexyl trifluoroacetate -2-hydroxy-2- thien-2-ylacetoxy] -1-phenethyl-1-azoniabicyclo [2.2.2] octane 1- [3- (3-cyanophenoxy) propyl] - (3R) -3 - [(2S) -2- (3R) -3 - [(2R) -2-cyclohexyl-2-hydroxy-2-hydroxy-2-thiazol-2-ylacetoxy] -1-azoniabicyclo [2.2.2] thien-2-ylacetoxy] -1- (3-phenoxypropyl) -1-azonia-bicyclo [2.2.2] octane (3R) -3 - [(2R) -2-cyclohexyl-2-hydroxy-2 2-yl-ethoxy] -1-phenethyl-1-azoniabicyclo [2.2.2] octane 1- [3- (3-cyanophenoxy) propyl] - (3R) -3 - [(2R) - 2-Cyclohexyl-2-hydroxy-2-thien-2-ylacetoxy] -1-azoniabicyclo [2.2.2] octane Trifluoroacetate (3R) -3- (2-hydroxy-4-phenyl-2-thien-2 (3S) -3 - [(2S) -2-cyclopentyl-2-hydroxy-2-thien-2-yl] -biphenyl- (3S) -3 - [(2S) -2-cyclopentyl-2-hydroxy-2-thien-2-yl] -2-cyclohexylpropyl) -1-azoniabicyclo [2.2.2] octane trifluoroacetate -ylacetoxy] -1- (3-thien-2-ylpropyl) -1-azoniabicyclo [2.2.2] octane (3S) - 3 - [(2S) -2-cyclopentyl-2-hydroxy-2-thien-2-ylacetoxy] -1- (3-phenylpropyl) -1-azonia-bicyclo [2.2.2] octane 4- [ (2R) -2-cyclohexyl-2-hydroxy-2-phenylacetoxy] -1- (3-thien-2-ylpropyl) -1-azonia-bicyclo [2.2.2] octane 4 - [(2R) -2-cyclohexyl-2-hydroxy-2-phenylacetoxy] -1- (3-phenoxypropyl) -1-azoniabicyclo [2.2.2] octane. A process for the production of a compound of formula (I): Wherein R 1, R 2, R 3, R 4, R 5, R 6, p, m, η, A, B and X are as defined in any one of claims 1 to 18, which process comprises the quaternization of the nitrogen of the azoniabicyclic ring of a compound of formula wherein R 4, R 5, R 6, and p are as defined above, with an alkylating agent of formula (II): wherein R 1, R 2, R 3, m, η, A and B are as defined above, and W represents a marda group. A process according to claim 21, wherein W represents a group X as defined in claims 1 or 13. A process according to claim 21 or claim 22, wherein the resulting reaction mixture is purified by solid phase extraction. ΡΕ1353919 18 A compound of formula (III) m wherein p, R4, R5 and R6 are as defined in claim 1, the substituent on the azabicyclo group is in the 3or 4-position and when in the 3-position this substituted carbon has an enantiomerically pure R or S configuration, from which when R 4 is a 3-thienyl group and R 5 is a cyclohexyl group and R 6 is not a hydroxide group. A compound according to claim 24, wherein the substituent on the azabicyclo group is in the 3-position in the R configuration. A compound according to claim 24, wherein the substituent on the azabicyclo group is in the 3-position with the S configuration. A compound according to any one of claims 24 to 26 wherein the carbon substituted with R 4, R 5 and R 6 has the R configuration. A compound according to any one of claims 19 to 133939, claims 24 to 26 wherein the carbon substituted with R 4, R 5 and R 6 has the S configuration. A compound according to any one of claims 24 to 28, which is a single isomer. A compound according to claim 24 which is: (2R) -2-Cyclopentyl-2-fur-2-yl-2 (3R) -1-azabicyclo [2.2.2] oct- (3R) -1-azabicyclo [2.2.2] oct-3-yl ester (2 S) -2-cyclopentyl-2-fur-2-yl-2-hydroxyacetic acid (3R) -1-azabicyclo [ (3R) -1-Aza-bicyclo [2.2.2] oct-3-enoic acid (2R) -2-cyclohexyl-2-fur- (2R) -2-cyclohexyl-1-azabicyclo [2.2.2] oct-4-yl ester (2S) -2-cyclohexyl- -2-hydroxy-2-phenylacetic acid A pharmaceutical composition comprising a compound according to any one of claims 1 to 20 in admixture with a pharmaceutically acceptable carrier or diluent. A compound according to any one of claims 1 to 20, or a pharmaceutical composition according to claim 31, for therapeutic use in a method of treatment of the human or animal body by therapy. 20 ΡΕ1353919 Use of a compound according to any one of claims 1 to 20, or a pharmaceutical composition according to claim 31, in the manufacture of a medicament for the treatment of a respiratory, urological or gastrointestinal disease or problem. A combination product comprising: (i) a compound according to any one of claims 1 to 20; and (ii) another compound effective in the treatment of a respiratory, urological or gastrointestinal disease or problem. A combination product according to claim 34 comprising (i) a compound according to any one of claims 1 to 20; and (ii) a β2 agonist, steroid, antiallergic drug, phosphodiesterase IV inhibitor and / or leukotriene D4 (LTD4) inhibitor for simultaneous, separate or sequential use in the treatment of a respiratory disease. Lisbon, September 29, 2006